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1
Adamolekun, Wole, J. A. Obadeyi, Sunday Oseiweh Ogbeide, and A. A. Akande. "Microfinance Institution (MFIs) and Survival of Micro and Small Enterprises (MSEs): Empirical Evidence of TraderMoni Scheme Beneficiaries in South-Western Nigeria." Advances in Social Sciences Research Journal 8, no. 3 (March 19, 2021): 195–215. http://dx.doi.org/10.14738/assrj.83.9723.
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Deregulation in Microfinance Institution (MFIs) in accordance with regulatory policy architecture since 2005 has not fully stimulated sustainability towards the informal system due to the inability of MFIs to access funds and government to judiciously administer credits to beneficiaries of various schemes; this has led to the partial collapse of some schemes in Nigeria; despite Government good intentions of creating employment and alleviating poverty. In view of this, this study assessed Microfinance Institution (MFIs) and Survival of Micro and Small Enterprises (MSEs): Empirical evidence of tradermoni scheme beneficiaries in South-Western Nigeria. The study adopted Tedeschi model (2006) that examined incentives available for borrowers to repay loans. Furthermore, reference was made to Markov Chain model to investigate the response of individual borrower as an applicant and beneficiary of tradermoni scheme in the context of this study. Eighteen MFIs were sampled from 2009 – 2020. Panel data was adopted for the study. The result showed mixed influences of MFIs on survival of MSEs. We are hopeful that findings of this paper would help to fill the existing gap on the influence of MFIs on the survival of MSEs.
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Tandelilin, Elsye, Dwi Ratmawati, and Tri Siwi Agustina. "An exploration of ethnic entrepreneurial values and characteristics in MSEs." BISMA (Bisnis dan Manajemen) 13, no. 2 (April 30, 2021): 148. http://dx.doi.org/10.26740/bisma.v13n2.p148-162.
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Entrepreneurship is one aspect that can encourage economic growth in a country through the creation of goods and services, it can improve the welfare of society. However, the survival of micro and small enterprises (MSEs) is still lower. Even though the number of MSEs in Indonesia has increased, the failure elevates. Variables that can increase the success of MSEs include the values and characteristics of the entrepreneur. This paper explores the entrepreneurial values and characteristics of Chinese, Javanese, and Madurese ethics in MSEs. This study uses a case study approach by using in-depth interviews to explore detailed information. The data source is primary data with six informants from three different ethnicities (Chinese, Javanese, and Madurese). The results demonstrate that Indonesian Chinese entrepreneurs uphold values and dominant perseverance, hard work, guanxi, honesty, personal trust, and confucianism values. Meanwhile, Javanese entrepreneur implements family values, spirituality, innate, paternalism, creativity, deliberation, and harmony. Finally, Madurese entrepreneur emphasizes obedience/surrender to parents, fraternity, and natural behaviour.
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Peter Kibas; Geoffrey Kamau, Martin Lubowa;. "Influence of Guerrilla Skills on Micro and Small Enterprise Survival in Wakiso District, Uganda." Editon Consortium Journal of Business and Management Studies 2, no. 1 (September 30, 2020): 69–80. http://dx.doi.org/10.51317/ecjbms.v2i1.149.
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This study examined the influence of Guerrilla skills on Micro and Small Enterprise (MSE) survival in Wakiso district, Uganda. The objective of the study was to establish the influence of guerrilla skills on profitability, stability and continuous resource availability of the Micro and Small Enterprises in Wakiso District, Uganda. Multiple sampling methods were used to derive a sample of 306 MSEs and a cross-sectional survey research design was used and adopted a positivist approach. The study used quantitative approaches which involved descriptive analysis (frequencies, percentages tables) and inferential statistics (linear regression). Raw data was captured into SPSS (version 16). Results revealed that Guerrilla skills had a positive and statistically significant influence on profitability, stability and continuous resource availability leading to increased enterprise survival. It also revealed that guerrilla skills have a positive and statistically significant influence on the survival of MSEs in Wakiso district, Uganda and accounted for 29.6 per cent of the variation in Micro and Small enterprise survival. MSE owner/managers need to develop, improve and utilize guerrilla skills in running their businesses. They should utilize resources within their surrounding maximally and be ahead of the competitors by utilizing unconventional low-cost tactics not known to their competitors and are difficult to copy. Similarly, programs to improve MSE owners/managers' guerrilla skills be implemented to enhance MSE survival. Curriculum developers need to design programs that will involve learners to apply guerrilla skills.
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AMAGWU, Francis Ibeawuchi, and Uzochukwu AMAKOM. "Determinants of Microfinance Sources by Micro and Small Enterprise (MSEs) Clusters in South-East Nigeria." Journal of Business Theory and Practice 7, no. 1 (December 19, 2018): 1. http://dx.doi.org/10.22158/jbtp.v7n1p1.
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<p><em>The source of microfinance is important and at the centre of every enterprise survival, profitability and growth that can trigger achievement of the expected roles and objectives. The main thrust of this study, therefore, is to understand the determinants of the choice of microfinance sources and level of support from funds providers. The study employed multi-stage sampling technique in identifying clusters from three cities (Onitsha, Aba and Nnewi) of the South East, Nigeria and generated relevant data through instruments such as questionnaire, personal interviews and Focused Group Discussions (FGDs). Using logit regression, the study found that interest rate, repayment period, amount or volume of capital and proximity to enterprises as the major determinants of the choice of microfinance source used by MSEs in South East, Nigeria. The study concluded that microfinance providers should be located closer to MSEs’ location for quicker response to their financing needs to the extent of taking advantage of social capital existing within the clusters as a possible cushion for the physical collaterals and documentations often requested for loan approvals. The study recommends that microfinance policy framework and interventions should encourage providers to locate closer to the enterprise clusters with the appropriate regulatory guarantee for operators.</em><em></em></p>
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Juárez Pérez, Sagrario. "Estudio cuasiexperimental de imagen pública en mypes de Tehuacán y la región." Revista Relayn - Micro y Pequeñas empresas en Latinoamérica 3, no. 2 (August 5, 2019): 17–24. http://dx.doi.org/10.46990/relayn.2019.3.2.61.
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El siguiente documento determina si los Mype empresarios de la zona de estudio pueden evaluar cuantitativamente la imagen Pública de las Mypes, a través de una investigación concluyente a partir de un cuasi experimento. Se hace la investigación con tres cientos ochenta y cuatro empresarios, los resultados son alentadores puesto que logran medir la comunicación verbal y no verbal, así como las imágenes subordinadas de la Imagen Pública, además, hacen recomendaciones que pueden mejorar las empresas utilizadas como estímulos, lo que nos permite inferir que la información puede ser utilizada para la mejora de sus propias empresas, generar capital intangible e incrementar la sobrevivencia de las mismas. AbstractThe following document determines if the MSes entrepreneurs of the study area can quantitatively evaluate the Public image of the MSes, through a conclusive investigation from a quasi-experiment. The research is done with six mype entrepreneurs, the results are encouraging since they manage to measure the verbal and non-verbal communication as well as the subordinate images of the Public Image, in addition, they make recommendations that can improve the companies used as stimuli, which allows us to infer that the information can be used to improve their own companies, generate intangible capital and increase their survival.
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Prasetyo, Hendrawan. "IMPLEMENTASI KEBIJAKAN UPAH MINIMUM KABUPATEN (UMK) DAN PENGARUHNYA TERHADAP KESEJAHTERAAN MASYARAKAT (Studi Pada Kabupaten Kebumen)." Fokus Bisnis : Media Pengkajian Manajemen dan Akuntansi 17, no. 2 (January 2, 2019): 25–32. http://dx.doi.org/10.32639/fokusbisnis.v17i2.272.
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Almost the average company in Kebumen Regency has applied salary payment of employees in accordance with the provisions of MSEs, although in implementation is not one hundred percent. Although Kebumen District Government has set District Minimum Wage (MSE) in 2017 amounting to Rp 1,433,900.00, but there are still many employers / companies that pay salaries under the MSEs. The relations of workers and employers actually need each other. Workers expect the fulfillment of the necessities of life and the entrepreneur seeks to maintain the survival of his company. Without employers, workers find it difficult to sustain their lives, whereas unemployed workers will not be able to continue their business. So it needs a good relationship between the two, the existence of mutual understanding. Employers need to understand the needs of the workers, and the workers understand the company's ability to pay wages. The purpose of this study is to find out how the implementation of District Minimum Wage policy and its impact on community welfare in Kebumen District. The type of this research is qualitative research, taking the data source using the technique of "purposive sampling" with the number of informants as many as 11 people including from the elements of local government that is the Office of Manpower and Cooperative SME Kebumen Regency, private entrepreneurs in Kebumen District, and employees of private companies in Kebumen . Data collection in this research is done through observation, documentation and in-depth interview. Data analysis techniques in this study is interactive model analysis, including four components of data collection, data reduction, data presentation and conclusion or verification. Theories used are theories of public policy, policy implementation and wages. The results of this study found that almost most companies in Kebumen District have paid employee salaries according to MSEs, although there are still companies that have not been able to meet the payroll of employees according to the MSEs. Some companies studied do not experience obstacles in the implementation of MSE in accordance with the established, but if the company has problems in terms of implementing payroll employees according to MSEs there is a mechanism of deferring payment. The role of local government in the implementation of MSE is needed in terms of socialization and coaching and know the problems that occur in the company or labor in the scope of Kebumen. In terms of achieving the welfare of workers, the company should be able to provide salaries in accordance with the Minimum Wage and supplemented with the provision of various benefits in order to create the welfare of workers in particular and society in general.
Keywords: policy implementation, workers, company, welfare, minimum wage
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Hingorani, Sunil R., William Proctor Harris, J. Thaddeus Beck, Boris A. Berdov, Stephanie Ann Wagner, Eduard M. Pshevlotsky, Sergei Tjulandin, et al. "A phase Ib study of gemcitabine plus PEGPH20 (pegylated recombinant human hyaluronidase) in patients with stage IV previously untreated pancreatic cancer." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 4010. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.4010.
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4010 Background: PEGPH20 is a PEGylated version of human recombinant hyaluronidase. In preclinical studies, PEGPH20 depleted pancreatic cancers of their high hyaluronan (HA) content. In a genetically-engineered murine model of PDA, PEGPH20 + gemcitabine (Gem) significantly prolonged survival compared to Gem alone. In Ph1 PEGPH20 monotherapy studies, the MTD was 3.0 μg/kg. The most common AEs were musculoskeletal events (MSEs). Methods: This was a dose-escalation study to find the recommended Phase 2 dose (RP2D) of PEGPH20 in combination with Gem in patients (pts) with Stage IV previously untreated pancreatic cancer. Pts received PEGPH20 at 1, 1.6, or 3 μg/kg IV twice a week for Wks 1-4, weekly for Wks 5-7, then 1 wk rest. Dose escalation was based on safety. Gem was given at 1000 mg/m2 IV once a week for Wks 1-7, then 1 wk rest. Thereafter, PEGPH20 + Gem were given once a week for 3 wks in 4-wk cycles. Dexamethasone was given pre and post PEGPH20 doses. Results: Of the 28 pts enrolled, the majority had a Karnofsky performance status of 80%, and 85%/19%/26% of pts had liver/lung/visceral metastases. The median age was 58 yrs. Four pts received PEGPH20 at 1 μg/kg, 4 at 1.6 μg/kg, and 20 at 3 μg/kg. The RP2D was 3 μg/kg. Treatment duration ranged from 1-274 days; 5 pts remain on study. Treatment was generally well tolerated. Ten pts had 1 Gem dose reduction, 2 pts had 1 PEGPH20 dose reduction (3 to 1.6 µg/kg), but no pt had a DLT. The most common PEGPH20-related AEs were MSEs (25% Gr1; 18% Gr2) and fatigue (21% Gr1; 11% Gr2). Objective response was assessed by an independent central radiologist using RECIST 1.1. Of the 21 pts evaluable for efficacy, 7 had partial response (PR) for an overall response rate (ORR) of 33%, and 9 had stable disease for ≥ 2 mo. Tumor biopsies from 12 pts were evaluable for HA staining. HA was high in 9 and low in 3. Of the 9 with high HA staining, 5 had PR (56% ORR); HA data were not available for the other 2 PR pts. PK results show dose-dependent exposure consistent with data from PEGPH20 monotherapy studies. Conclusions: PEGPH20 in combination with Gem is generally well tolerated in advanced pancreatic cancer and shows promising efficacy, especially in pts with high intratumoral HA content. Clinical trial information: NCT01453153.
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Berne, Davi França, Roberto Coda, Patricia Krakauer, and Denis Donaire. "The innovation challenge in micro and small enterprises (MSE)." Innovation & Management Review 16, no. 3 (August 28, 2019): 235–52. http://dx.doi.org/10.1108/inmr-03-2019-0031.
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Purpose This study aims to measure the degree of innovation of micro and small industrial companies in the West and Southwest metropolitan regions of the city of São Paulo, through a survey with 203 firms in the metallurgy sector. Design/methodology/approach The research had a quantitative and descriptive focus and used as methodology the validated and international approach known as Innovation Radar. Findings The degree of innovation in these micro and small companies is low; thus, the authors could not characterize them as systemic innovators. Most of them are little innovative, although some were classified as occasional innovators. The dimensions organization, processes, presence, supply chain and added value were the least developed. Research limitations/implications To carry out similar studies in other Brazilian regions, to compare results and draw new conclusions, or even check if the degree of innovation present in micro-firms of these regions would not be even lower; to monitor the evolution of companies through a longitudinal study, to detect improvements in the degree of innovation; and to conduct a qualitative research that can deepen questions on the results of our study, such as the reasons why this type of company does not adopt innovative practices, or even the real suitability of the Innovation Radar model for micro and small enterprises (MSEs). We observed that some dimensions proved to be too sophisticated for these companies, such as R&D investments and the adoption of technological advances. Practical implications The study shows that the degree of innovation measured by the Innovation Radar is a useful and initial measure to check an innovative attitude in micro and small companies. It can also drive the actions that should be prioritized to stimulate the culture of innovation in SME. However, it does not allow to answer why this type of organization does not adopt innovative practices as a management attitude. Regarding its contribution, the authors expect that the paper may bring an awareness of managers and owners of micro and small companies for the need to foster innovative practices that can help increase the competitiveness and survival of this type of organization. Social implications In Brazil, despite the fact that MSEs represent 98 per cent of the existing companies, and are mainly responsible for job creation, their leaders have a low concern for innovative practices. Originality/value The study contributes to identify the degree of innovation of these firms, which comprise a representative and strategic segment of the city’s economy, by checking to what extent an innovative attitude is effectively present in this sector. The theoretical contribution of this study regards the appropriateness of mechanisms or methodologies created to measure the degree of innovation in large organizations. Dimensions such as technological platform, brand, innovative ambience, degree of organization or systematization of processes, which are frequently considered for companies in general, and especially for large ones, are not sufficient or, instead, too sophisticated to allow an effective measurement of the degree of innovation in MSE. Thus, this study provides information for designing more effective ways to evaluate the degree of innovation that take into account MSE’s specificities, which can be considered innovation efforts, such as simple process improvements, professional development of teams, and actions to seize ideas and opportunities, among others.
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Miroshnichenko, Svetlana, Ivan Usynin, Alexey Dudarev, Vadim Nimaev, and Anastasiya Solovieva. "Apolipoprotein A-I Supports MSCs Survival under Stress Conditions." International Journal of Molecular Sciences 21, no. 11 (June 5, 2020): 4062. http://dx.doi.org/10.3390/ijms21114062.
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Clinical trials have shown the safety of mesenchymal stem/stromal cells (MSCs) transplantation, but the effectiveness of these treatments is limited. Since, transplanted MSCs will undergo metabolic disturbances in the bloodstream, we investigated the influence of blood plasmas of type 2 diabetes (T2D) patients on MSCs viability and examined whether apolipoprotein A-I (apoA-I) could protect cells from stressful conditions of serum deprivation (SD), hypoxia, and elevated concentrations of reactive oxygen species (ROS). ApoA-I exhibits anti-inflammatory, immune activities, improves glycemic control, and is suitable for T2D patients but its influence on MSCs remains unknown. For the first time we have shown that apoA-I decreases intracellular ROS and supports proliferative rate of MSCs, thereby increasing cell count in oxidation conditions. ApoA-I did not influence cell cycle when MSCs were predominantly in the G0/G1 phases under conditions of SD/hypoxia, activated proliferation rapidly, and reduced apoptosis during MSCs transition to the oxygenation or oxidation conditions. Finally, it was found that the blood plasma of T2D individuals had a cytotoxic effect on MSCs in 39% of cases and had a wide variability of antioxidant properties. ApoA-I protects cells under all adverse conditions and can increase the efficiency of MSCs transplantation in T2D patients.
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Copland, Ian B., Jessica Cuerquis, Eugenia Wang, and Jacques Galipeau. "Genomic, Proteomic and Functional Screens Identify PAI-1 as an Important Factor Influencing Mesenchymal Stromal Cell Survival Post-Transplantation In Vivo." Blood 110, no. 11 (November 16, 2007): 180. http://dx.doi.org/10.1182/blood.v110.11.180.180.
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Abstract MSCs have robust reparative properties through their ability to limit apoptosis, enhance angiogenesis and direct positive tissue remodelling. However, a major limitation on the widespread application of MSC transplantation is that transplanted cells have low survival rates in vivo. Thus, enhancing MSCs survival post-transplantation is critical for the successful implementation of cellular therapy. One explanation for their low survival is that MSCs are often transplanted into ischemic tissue - such as infarcted myocardium - where there is poor blood supply and low oxygen tension. How these factors influence MSC survival is still unclear, therefore the objective of this project was to better understand how hypoxia under low nutrient conditions affects the behaviour and survival of MSCs. To answer this question, we performed the following series of experiments: Isolate and immunophenotype murine MSCs. Assess impact of in vitro ischemic conditions (hypoxia and serum deprivation) on MSCs by microarray analysis and ITRAQ proteomics for secreted proteins. Confirm changes of specific factors in vitro. Isolate and immunophenotype MSCs from knock-out mice for specific factors. Determine whether knock-out MSCs have altered survival in vitro and in vivo. As confirmed by PCR and Western blotting, microarray and proteomic screens, identified plasminogen activator inhibitor-1 (PAI-1) as one factor consistently upregulated in hypoxia (3% oxygen) treated MSCs. In vitro migration studies demonstrated that PAI-1 blocks migration of MSCs towards a chemotactic gradient, while isolation of PAI-1 knock-out MSCs, revealed an enhanced survival of PAI-1null MSCs over wild-type MSCs. In vivo subcutaneous transplantation of beta-galactosidase engineered wild-type and PAI-1null MSCs, recapitulated our in vitro results, such that 14 days post-implantation PAI-1null MSCs had a five fold increase in survival compared to wild-type MSCs. In conclusion, PAI-1 is a multifunctional protein. As an inhibitor, PAI-1 acts as ‘bait’ regulating the conversion of plasminogen to plasmin thus functioning as a major control point in the regulation of systemic fibrinolysis and local growth factor availability. In addition, PAI-1 can also act as a ligand for vitronectin to influence cellular migration/adhesion. Up-regulation of PAI-1 by MSCs after transplantation impacts MSC survival. Determining how to block PAI-1 following transplantation of MSCs is currently under investigation.
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Huang, Yan, Zuo Liu, Fengbo Tan, Zhiping Hu, and Ming Lu. "Effects of the Insulted Neuronal Cells-Derived Extracellular Vesicles on the Survival of Umbilical Cord-Derived Mesenchymal Stem Cells following Cerebral Ischemia/Reperfusion Injury." Oxidative Medicine and Cellular Longevity 2020 (July 17, 2020): 1–26. http://dx.doi.org/10.1155/2020/9768713.
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Umbilical cord-derived mesenchymal stem cells (UC-MSCs) engraftment is a potential therapy for cerebral ischemic stroke. However, the harsh microenvironment induced by cerebral ischemia/reperfusion restricts the survival rate and therapeutic efficiency of the engrafted UC-MSCs. In this study, we explored whether small extracellular vesicles (EVs) derived from injured neuronal cells following exposure to cerebral ischemia/reperfusion insult affect the survival of transplanted UC-MSCs. To establish a simulation of cerebral ischemia/reperfusion microenvironment comprising engrafted UC-MSCs and neuronal cells, we cocultured EVs derived from injured N2A cells, caused by exposure to oxygen-glucose deprivation and reperfusion (OGD/R) insult, with UC-MSCs in a conditioned medium. Coculture of UC-MSCs with EVs exacerbated the OGD/R-induced apoptosis and oxidative stress. Suppression of EVs-release via knock-down of Rab27a effectively protected the UC-MSCs from OGD/R-induced insult. Moreover, hypoxia preconditioning not only elevated the survival of UC-MSCs but also improved the paracrine mechanism of injured N2A cells. Altogether, these results show that EVs from injured N2A cells exacerbates OGD/R-induced injury on transplanted UC-MSCs in vitro. Hypoxia preconditioning enhances the survival of the engrafted-UC-MSCs; hence, thus could be an effective approach for improving UC-MSCs therapy in ischemic stroke.
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Yang, Xiaodong, Ilango Balakrishnan, Beverly Torok-Storb, and Manoj M. Pillai. "Marrow Stromal Cell Infusion Rescues Hematopoiesis in Lethally Irradiated Mice despite Rapid Clearance after Infusion." Advances in Hematology 2012 (2012): 1–5. http://dx.doi.org/10.1155/2012/142530.
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Marrow stromal cells (MSCs, also termed mesenchymal stem cells) have been proposed as a promising cellular therapy for tissue injury including radiation-induced marrow failure, but evidence for a direct effect is lacking. To assess the effects of MSCs on survival after lethal irradiation, we infused syngeneic MSCs (either as immortalized MSCs clones or primary MSCs) intravenously into wild-type C57/Bl6 mice within 24 hours of lethal total body irradiation (TBI). Mice receiving either of the MSC preparations had significantly improved survival when compared to controls. In vivo imaging, immune histochemistry, and RT-PCR employed to detect MSCs indicated that the infused MSCs were predominantly localized to the lungs and rapidly cleared following infusion. Our results suggest that a single infusion of MSCs can improve survival after otherwise lethal TBI but the effect is not due to a direct interaction with, or contribution to, the damaged marrow by MSCs.
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El Haddad, Najib, Dean Heathcote, Robert Moore, Sunmi Yang, Jamil Azzi, Bechara Mfarrej, Mark Atkinson, et al. "Mesenchymal stem cells express serine protease inhibitor to evade the host immune response." Blood 117, no. 4 (January 27, 2011): 1176–83. http://dx.doi.org/10.1182/blood-2010-06-287979.
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Abstract Clinical trials using mesenchymal stem cells (MSCs) have been initiated worldwide. An improved understanding of the mechanisms by which allogeneic MSCs evade host immune responses is paramount to regulating their survival after administration. This study has focused on the novel role of serine protease inhibitor (SPI) in the escape of MSCs from host immunosurveillance through the inhibition of granzyme B (GrB). Our data indicate bone marrow–derived murine MSCs express SPI6 constitutively. MSCs from mice deficient for SPI6 (SPI6−/−) exhibited a 4-fold higher death rate by primed allogeneic cytotoxic T cells than did wild-type MSCs. A GrB inhibitor rescued SPI6−/− MSCs from cytotoxic T-cell killing. Transduction of wild-type MSCs with MigR1-SPI6 also protected MSCs from cytotoxic T cell–mediated death in vitro. In addition, SPI6−/− MSCs displayed a shorter lifespan than wild-type MSCs when injected into an allogeneic host. We conclude that SPI6 protects MSCs from GrB-mediated killing and plays a pivotal role in their survival in vivo. Our data could serve as a basis for future SPI-based strategies to regulate the survival and function of MSCs after administration and to enhance the efficacy of MSC-based therapy for diseases.
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Park, Gyeongsin, Byunghoo Song, Yuji Lee, Ahwon Lee, Yang-Guk Chung, Chang Suk Kang, and Il-Hoan Oh. "Stromal Interaction of Lymphoma Cells Regulates Survival and Chemoresistance." Blood 118, no. 21 (November 18, 2011): 5195. http://dx.doi.org/10.1182/blood.v118.21.5195.5195.
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Abstract Abstract 5195 High-grade lymphomas are aggressive but largely curable, whereas low-grade lymphomas are indolent, but frequently recur to be incurable, paradoxically. Mesenchymal stromal cells (MSCs) have been known to participate for reconstituting microenvironment. Studies show that signalings between normal lymphoid cells and stromal cells were frequently altered in high grade lymphomas, but relatively conserved in low grade lymphomas. However, which cell and mechanism is responsible for lymphoma recurrence remains unclear. Here we hypothesized that the interaction with stroma may play a role for lymphoma cell growth and survival. For this, we investigated the effect of MSCs on lymphoma cell growth and chemo-resistance by using a coculture system with MSCs (derived from tonsil), as a stromal microenvironment for lymphoma cells. First, coculture of lymphoma cell line (Pfeiffer) and primary lymphoma cells with/without MSCs for 3 days showed that the MSC-cocultured cells grew more rapidly (1.4 times and 1.8 times for Pfeiffer and primary cells, respectively) than MSC-free lymphoma cells. To further investigate the underlying mechanism of promoting growth, lymphoma cells were cocultured with MSCs in the presence or absence of transwell filter. At day 4, the proliferation of lymphoma cells in the absence of transwell was 3.5 times higher than in the presence of transwell. Interestingly, the lymphoma cells cocultured with MSCs showed increased expression of CXCR4 compared with lymphoma cells cultured alone. When the cyto-protective effect of MSCs was examined by doxorubicin treatment (1ug/ml) in the presence or absence of MSCs, 91% of MSC-cocultured cells survived, whereas only 28% of stroma-free cultured cells survived. These results demonstrate that the direct contact interaction with stroma might be important for lymphoma cell growth and survival. In conclusion, our data suggest that the interaction with stromal microenvironment is an important factor for survival of lymphoma cells which cells might be responsible for chemoresistance, and raise the possibility that the stromal interaction could be a potential target for lymphoma treatment. Disclosures: No relevant conflicts of interest to declare. This research was supported by a grant (10172KFDA993) from Korea Food & Drug Administration in 2011. Disclosures: No relevant conflicts of interest to declare.
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Moloney, Teresa C., Peter Dockery, Anthony J. Windebank, Frank P. Barry, Linda Howard, and Eilís Dowd. "Survival and Immunogenicity of Mesenchymal Stem Cells From the Green Fluorescent Protein Transgenic Rat in the Adult Rat Brain." Neurorehabilitation and Neural Repair 24, no. 7 (April 8, 2010): 645–56. http://dx.doi.org/10.1177/1545968309357745.
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Background. A major technical limitation in preclinical cell replacement research is the ability to discriminate between donor and host tissue after transplantation. This problem has been lessened by the availability of transgenic animals that express “reporter” genes, such as green fluorescent protein (GFP). Objective. We determined the usefulness of one such transgenic reporter rat to assess the survival of bone marrow—derived rat mesenchymal stem cells (MSCs) following direct transplantation into the intact adult brain. We also sought to determine if the expression of GFP in the brain affected the survival of the MSCs or the host’s neuroimmune response to the cells. Methods. Rats received intrastriatal injections of sterile transplantation medium, 100 000 normal MSCs, or 100 000 GFP-MSCs and were killed humanely 1, 4, 7, 28, and 42 days posttransplantation for astrocyte and microglial immunohistochemical staining. Results. GFP-MSCs were evident at each examination, although their survival declined over time. Graft volume estimates comparing normal and GFP-MSCs revealed that GFP expression did not adversely affect the survival of the stem cells in the brain. Furthermore, immunostaining for astrocytes and microglia revealed that expression of the reporter protein did not affect the immunogenicity of the stem cells. Conclusions. These data indicate the usefulness of GFP for investigating the survival of MSCs following transplantation to the brain. However, the mechanisms responsible for the poor survival of the stem cells must be elucidated if these cells are to serve cell-based therapies for neurodegenerative disorders.
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Singh, Pratibha, Seiji Fukuda, Mary R. Saunders, and Louis M. Pelus. "Survivin Is a Master Regulator of Mesenchymal Stem Cell Functions and Potential Therapeutic Target for Mesenchymal Stem Cell Expansion." Blood 124, no. 21 (December 6, 2014): 774. http://dx.doi.org/10.1182/blood.v124.21.774.774.
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Mesenchymal stemcells (MSCs) are found throughout adult organisms and are involved in tissue maintenance and repair, as well as in the regulation of hematopoiesis and immunologic responses. Several clinical trials are currently under way to use allogeneic MSCs for enhancement of hematopoietic stem cell transplantation and treatment of graft-versus-host disease, spinal cord injury, cartilage and meniscus repair, and stroke. However, the therapeutic uses of MSCs can be limited by insufficient MSC number, their survival, and their ability to differentiate into multiple lineages, pointing to an important need to identify factors regulating MSC survival, proliferation, and differentiation. In this study, we explored the role of the anti-apototic protein Survivin in MSC functions. Survivin is an intracellular member of the inhibitor-of-apoptosis protein (IAP) family and is implicated in regulation of apoptosis, cell division, and cell cycle control of many cell types including hematopoietic stem cells, leukemic cells, and endothelial cells. However, whether Survivin is involved in MSC activity or function is unknown. Using flow cytometry and function assays, we found that adult mouse and human MSCs, identified as CD45-Ter119-CD51+PDGFR+Nestin+ cells, express high levels of Survivin, which regulates MSCs survival and expansion under normal physiological and stressful conditions. Flow cytometry analysis revealed that approximately 40.5±3.6% of mouse bone marrow MSCs, 33.6±4.2% of adult human bone marrow MSCs, and 43.6±5.3% human cord blood MSCs express Survivin. Treatment of mice in vivo with YM155 (10 mg/kg), a small molecule Survivin inhibitor, for 6 days decreased bone marrow CD45-Ter119-CD51+PDGFR+Nestin+ MSC by 2.1 fold and functional fibroblast colony formation (CFU-F) by 2.8 fold. Survivin gene deletion using Survivin-specific SiRNA decreased mouse and human bone marrow derived MSCs number and CFU-F ability by 3.2 fold and 2.8 fold respectively. Retroviral overexpression of Survivin in mouse MSCs enhanced CFU-F formation by 4 fold. In an in vitro wound healing assay YM155-treated MSCs recovered more slowly compared to control cultures. To determine underlying mechanisms involved in Survivin dependent regulation of MSC function, we measured the survival and proliferation of YM155 treated MSCs. Treatment of mouse or human bone marrow-derived MSCs with YM155 (50 nmol/l) for 48 hours enhanced the caspase 3 and 7 expression by 42.8% and 63.9% respectively, while BrdU incorporation was similar in control and YM155-treated MSCs, suggesting that Survivin is primarily involved in MSC survival. To explore whether Survivin is also involved in growth factor-mediated MSC survival and expansion, mouse bone marrow derived MSCs were cultured in the presence of platelet derived growth factor (PDGF) or basic fibroblast growth factor (b-FGF) with or without the Survivin inhibitor YM155. PDGF enhanced the Survivin expression by 52.8±2.2% and b-FGF enhanced Survivin expression by 43.8±4.5% and increased the CFU-F counts by 5.6 fold and 4.2 fold, respectively. In contrast, YM155 treated MSCs did not show any enhancement in Survivin expression, and CFU-F were substantially lower than the corresponding controls (PDGF or b-FGF treated cultures). To determine whether Survivin affects the Survival of stressed MSCs, we exposed mouse bone marrow MSCs to 4 Gy irradiation dose and followed by culture for 3 days with or without the Survivin inhibitor YM155. Irradiation alone reduced the survival of MSCs by 53.5%, however the viability of irradiated MSCs treated with YM155 was reduced by 82.8%. The hallmark of MSC function is the capacity to differentiate into several mesodermal lineages. We found that the exposure of MSC cultures to YM155 during the lineage differentiation process inhibits MSC osteogenic and adipogenic differentiation while sparing chondrogenic cell differentiation. In conclusion, our study demonstrates that Survivin controls basal and growth factor dependent survival and expansion of mouse and human MSCs, and protects them from irradiation induced cell death. Furthermore, our data suggest the regulating Survivin expression in MSCs would be beneficial to enhance MSC recovery for clinical utility. Disclosures No relevant conflicts of interest to declare.
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Abe, Takaharu, Keisuke Sumi, Ryo Kunimatsu, Nanae Oki, Yuji Tsuka, Tetsuya Awada, Kengo Nakajima, Masaru Sugiyama, and Kotaro Tanimoto. "Bone Regeneration in a Canine Model of Artificial Jaw Cleft Using Bone Marrow–Derived Mesenchymal Stem Cells and Carbonate Hydroxyapatite Carrier." Cleft Palate-Craniofacial Journal 57, no. 2 (August 18, 2019): 208–17. http://dx.doi.org/10.1177/1055665619868868.
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Objective: Cleft lip and palate (CLP) is a common anomaly of the orofacial region. Mesenchymal stem cell (MSC) transplantation has been a focus of regenerative medicine, and its application to the repair of bone defects in patients with CLP is highly anticipated. This study investigated the potential for using MSCs to regenerate bone in a jaw cleft as well as the survival of transplanted MSCs using a canine model of CLP. Design: Mesenchymal stem cells collected from the bone marrow of beagle dogs were transplanted along with carbonate hydroxyapatite into jaw clefts in beagle dogs. Mesenchymal stem cells labeled with fluorescent silica nanoparticles were also transplanted, and a histological analysis was performed 3 months later to evaluate MSC survival. Results: Carbonate hydroxyapatite regeneration into bone was enhanced by cotransplantation of MSCs. The survival rate of MSCs transplanted after 3 months was 5.7%. Conclusions: Transplanted MSCs promote bone regeneration, although their survival rate is low.
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Tang, Yaohui, Beibei Cai, Falei Yuan, Xiaosong He, Xiaojie Lin, Jixian Wang, Yongting Wang, and Guo-Yuan Yang. "Melatonin Pretreatment Improves the Survival and Function of Transplanted Mesenchymal Stem Cells after Focal Cerebral Ischemia." Cell Transplantation 23, no. 10 (October 2014): 1279–91. http://dx.doi.org/10.3727/096368913x667510.
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Mesenchymal stem cell (MSC) transplantation has been shown to be beneficial in treating cerebral ischemia. However, such benefit is limited by the low survival of transplanted MSCs in an ischemic microenvironment. Previous studies showed that melatonin pretreatment can increase MSC survival in the ischemic kidney. However, whether it will improve MSC survival in cerebral ischemia is unknown. Our study examined the effect of melatonin pretreatment on MSCs under ischemia-related conditions in vitro and after transplantation into ischemic rat brain. Results showed that melatonin pretreatment greatly increased survival of MSCs in vitro and reduced their apoptosis after transplantation into ischemic brain. Melatonin-treated MSCs (MT-MSCs) further reduced brain infarction and improved neurobehavioral outcomes. Angiogenesis, neurogenesis, and the expression of vascular endothelial growth factor (VEGF) were greatly increased in the MT-MSC-treated rats. Melatonin treatment increased the level of p-ERK1/2 in MSCs, which can be blocked by the melatonin receptor antagonist luzindole. ERK phosphorylation inhibitor U0126 completely reversed the protective effects of melatonin, suggesting that melatonin improves MSC survival and function through activating the ERK1/2 signaling pathway. Thus, stem cells pretreated by melatonin may represent a feasible approach for improving the beneficial effects of stem cell therapy for cerebral ischemia.
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Takahashi, Ai, Hideaki Nakajima, Kenzo Uchida, Naoto Takeura, Kazuya Honjoh, Shuji Watanabe, Makoto Kitade, Yasuo Kokubo, William E. B. Johnson, and Akihiko Matsumine. "Comparison of Mesenchymal Stromal Cells Isolated from Murine Adipose Tissue and Bone Marrow in the Treatment of Spinal Cord Injury." Cell Transplantation 27, no. 7 (June 27, 2018): 1126–39. http://dx.doi.org/10.1177/0963689718780309.
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The use of mesenchymal stromal cell (MSC) transplantation to repair the injured spinal cord has shown consistent benefits in preclinical models. However, the low survival rate of grafted MSC is one of the most important problems. In the injured spinal cord, transplanted cells are exposed to hypoxic conditions and exposed to nutritional deficiency caused by poor vascular supply. Also, the transplanted MSCs face cytotoxic stressors that cause cell death. The aim of this study was to compare adipose-derived MSCs (AD-MSCs) and bone marrow-derived MSCs (BM-MSCs) isolated from individual C57BL6/J mice in relation to: (i) cellular characteristics, (ii) tolerance to hypoxia, oxidative stress and serum-free conditions, and (iii) cellular survival rates after transplantation. AD-MSCs and BM-MSCs exhibited a similar cell surface marker profile, but expressed different levels of growth factors and cytokines. To research their relative stress tolerance, both types of stromal cells were incubated at 20.5% O2 or 1.0% O2 for 7 days. Results showed that AD-MSCs were more proliferative with greater culture viability under these hypoxic conditions than BM-MSCs. The MSCs were also incubated under H2O2-induced oxidative stress and in serum-free culture medium to induce stress. AD-MSCs were better able to tolerate these stress conditions than BM-MSCs; similarly when transplanted into the spinal cord injury region in vivo, AD-MSCs demonstrated a higher survival rate post transplantation Furthermore, this increased AD-MSC survival post transplantation was associated with preservation of axons and enhanced vascularization, as delineated by increases in anti-gamma isotype of protein kinase C and CD31 immunoreactivity, compared with the BM-MSC transplanted group. Hence, our results indicate that AD-MSCs are an attractive alternative to BM-MSCs for the treatment of severe spinal cord injury. However, it should be noted that the motor function was equally improved following moderate spinal cord injury in both groups, but with no significant improvement seen unfortunately following severe spinal cord injury in either group.
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Templeton, Kayla, Meiby Ramos, Jacqueline Rose, Bryan Le, Qingwen Zhou, Amin Cressman, Stephanie Ferreyra, Carlito B. Lebrilla, and Fernando Antonio Fierro. "Mesenchymal Stromal Cells Regulate Sialylations of N-Glycans, Affecting Cell Migration and Survival." International Journal of Molecular Sciences 22, no. 13 (June 26, 2021): 6868. http://dx.doi.org/10.3390/ijms22136868.
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N-Glycosylations are an important post-translational modification of proteins that can significantly impact cell function. Terminal sialic acid in hybrid or complex N-glycans has been shown to be relevant in various types of cancer, but its role in non-malignant cells remains poorly understood. We have previously shown that the motility of human bone marrow derived mesenchymal stromal cells (MSCs) can be modified by altering N-glycoforms. The goal of this study was to determine the role of sialylated N-glycans in MSCs. Here, we show that IFN-gamma or exposure to culture media low in fetal bovine serum (FBS) increases sialylated N-glycans, while PDGF-BB reduces them. These stimuli alter mRNA levels of sialyltransferases such as ST3Gal1, ST6Gal1, or ST3Gal4, suggesting that sialylation of N-glycans is regulated by transcriptional control of sialyltransferases. We next show that 2,4,7,8,9-pentaacetyl-3Fax-Neu5Ac-CO2Me (3F-Neu5Ac) effectively inhibits sialylations in MSCs. Supplementation with 3F-Neu5Ac increases adhesion and migration of MSCs, as assessed by both videomicroscopy and wound/scratch assays. Interestingly, pre-treatment with 3F-Neu5Ac also increases the survival of MSCs in an in vitro ischemia model. We also show that pre-treatment or continuous treatment with 3F-Neu5Ac inhibits both osteogenic and adipogenic differentiation of MSCs. Finally, secretion of key trophic factors by MSCs is variably affected upon exposure to 3F-Neu5Ac. Altogether, our experiments suggest that sialylation of N-glycans is tightly regulated in response to environmental cues and that glycoengineering MSCs to reduce sialylated N-glycans could be beneficial to increase both cell migration and survival, which may positively impact the therapeutic potential of the cells.
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Halm, Darius, Nico Leibig, Jens Martens, G. Björn Stark, Tobias Groß, Stefan Zimmermann, Günter Finkenzeller, and Florian Lampert. "Direct comparison of the immunogenicity of major histocompatibility complex-I and -II deficient mesenchymal stem cells in vivo." Biological Chemistry 402, no. 6 (February 5, 2021): 693–702. http://dx.doi.org/10.1515/hsz-2020-0306.
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Abstract Mesenchymal stem cells (MSCs) play an important role in tissue engineering applications aiming at the regeneration or substitution of damaged tissues. In this context, off-the-shelf allogeneic MSCs would represent an attractive universal cell source. However, immune rejection is a major limitation for the clinical use of allogeneic MSCs. Immune rejection is mediated by the expression of major histocompatibility complexes (MHC)-I and -II on the donor cells. In this study, we eliminated MHC-I and/or MHC-II expression in human MSCs by using the CRISPR/Cas9 technology and investigated the effect of the individual or combined knockout of MHC-I and MHC-II on MSC survival after transplantation into immunocompetent mice. Elimination of MHC-I and/or MHC-II expression did not affect mesenchymal marker gene expression, viability, proliferation and the differentiation potential of MSCs in vitro. However, cell survival of transplanted MSCs was significantly elevated in MHC-I and MHC-II deficient MSCs. A direct side-by-side comparison does not reveal any significant difference in the immunogenicity of MHC-I and MHC-II knockout MSCs. Moreover, double knockout of MHC-I and MHC-II did not further increase in vivo cell survival of transplanted MSCs. Our results demonstrate that knockout of MHC-I and/or MHC-II represents an effective strategy to prevent immune rejection of allogeneic MSCs.
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Hao, Dake, Chuanchao He, Bowen Ma, Lee Lankford, Lizette Reynaga, Diana L. Farmer, Fuzheng Guo, and Aijun Wang. "Hypoxic Preconditioning Enhances Survival and Proangiogenic Capacity of Human First Trimester Chorionic Villus-Derived Mesenchymal Stem Cells for Fetal Tissue Engineering." Stem Cells International 2019 (November 12, 2019): 1–12. http://dx.doi.org/10.1155/2019/9695239.
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Prenatal stem cell-based regenerative therapies have progressed substantially and have been demonstrated as effective treatment options for fetal diseases that were previously deemed untreatable. Due to immunoregulatory properties, self-renewal capacity, and multilineage potential, autologous human placental chorionic villus-derived mesenchymal stromal cells (CV-MSCs) are an attractive cell source for fetal regenerative therapies. However, as a general issue for MSC transplantation, the poor survival and engraftment is a major challenge of the application of MSCs. Particularly for the fetal transplantation of CV-MSCs in the naturally hypoxic fetal environment, improving the survival and engraftment of CV-MSCs is critically important. Hypoxic preconditioning (HP) is an effective priming approach to protect stem cells from ischemic damage. In this study, we developed an optimal HP protocol to enhance the survival and proangiogenic capacity of CV-MSCs for improving clinical outcomes in fetal applications. Total cell number, DNA quantification, nuclear area test, and cell viability test showed HP significantly protected CV-MSCs from ischemic damage. Flow cytometry analysis confirmed HP did not alter the immunophenotype of CV-MSCs. Caspase-3, MTS, and Western blot analysis showed HP significantly reduced the apoptosis of CV-MSCs under ischemic stimulus via the activation of the AKT signaling pathway that was related to cell survival. ELISA results showed HP significantly enhanced the secretion of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) by CV-MSCs under an ischemic stimulus. We also found that the environmental nutrition level was critical for the release of brain-derived neurotrophic factor (BDNF). The angiogenesis assay results showed HP-primed CV-MSCs could significantly enhance endothelial cell (EC) proliferation, migration, and tube formation. Consequently, HP is a promising strategy to increase the tolerance of CV-MSCs to ischemia and improve their therapeutic efficacy in fetal clinical applications.
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Sequiera, Glen Lester, Niketa Sareen, Vikram Sharma, Arun Surendran, Ejlal Abu-El-Rub, Amir Ravandi, and Sanjiv Dhingra. "High throughput screening reveals no significant changes in protein synthesis, processing, and degradation machinery during passaging of mesenchymal stem cells." Canadian Journal of Physiology and Pharmacology 97, no. 6 (June 2019): 536–43. http://dx.doi.org/10.1139/cjpp-2018-0553.
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Increasing reports of successful and safe application of bone marrow derived mesenchymal stem cells (BM-MSCs) for cell therapy are pouring in from numerous studies. However poor survival of transplanted cells in the recipient has impaired the benefits of BM-MSCs based therapies. Therefore cell product preparation procedures pertaining to MSC therapy need to be optimized to improve the survival of transplanted cells. One of the important ex vivo procedures in the preparation of cells for therapy is passaging of BM-MSCs to ensure a suitable number of cells for transplantation, which may affect the turnover of proteins involved in regulation of cell survival and (or) death pathways. In the current study, we investigated the effect of an increase in passage number of BM-MSCs in cell culture on the intracellular protein turnover (protein synthesis, processing, and degradation machinery). We performed proteomic analysis of BM-MSCs at different passages. There was no significant difference observed in the ribosomal, protein processing, and proteasomal pathways related proteins in BM-MSCs with an increase in passage number from P3 to P7. Therefore, expansion of MSCs in the cell culture in clinically relevant passages (Passage 3–7) does not affect the quality of MSCs in terms of intracellular protein synthesis and turnover.
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Galvez Silva, Jorge, Mayela Mendt Vilchez, Imahashi Nobuhiko, Bruce R. Blazar, Patrick Zweidler-McKay, Katayoun Rezvani, and Elizabeth J. Shpall. "Ex-Vivo Fucosylation Improves the Anti-Graft-Versus-Host-Disease Effects of Mesenchymal Stem Cells in the NOD/SCID/IL-2R Null Mouse Model." Blood 128, no. 22 (December 2, 2016): 4559. http://dx.doi.org/10.1182/blood.v128.22.4559.4559.
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Abstract BACKGROUND: Graft versus host disease (GVHD) remains the major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HSCT). Due to their immunomodulatory properties, mesenchymal stem cells (MSCs) have produced durable responses in HSCT patients with steroid resistant GVHD, but their positive effects are not seen in all patients. Sackstein et al have shown that MSCs lack an E-selectin ligand on their surface, which impairs their ability to home to the bone marrow and potentially to sites of inflammation associated with GVHD. Our in vitro results confirmed that fucosylation markedly enhanced the E-selectin ligand expression on the MSC cell surface and did not adversely affected MSCs immunomodulatory properties. Hencewe postulated that ex-vivo fucosylation of MSCs would enhance their homing to sites of inflammantion and thus their clinical efficacy in our NOD/ SCID/IL-2R null (NSG) mouse model of GVHD. METHODS: On day -1 NSG mice were sub-lethally irradiated (300cGy) and infused with 2x106 fucosylated MSCs. Briefly, healthy bone marrow donor derived MSCs were treated for 30 minutes at room temperature with FT-VI (33ng/ml) and GDP-fucose (1mM) (Targazyme, Carlsbad, CA), and then washed prior to tail vein injection. Control mice received 2x106 unfucosylated MSCs or no MSCs. On day 0 all mice received 1x107 normal human donor peripheral blood mononuclear cells (PBMNCs), representing a MSCs:PBMNCs ratio of 1:5. Mice were then followed for weight loss, clinical GVHD score and survival. RESULTS: We found that a single dose of FT-VI treated MSCs reduced the acute severity of GVHD compared to unfucosylated MSCs and no MSCs (PBMNCs alone) in this xenogeneic mouse model. This was shown by prevention of weight loss (Fig. 1a), and lower GVHD scores (Fig 1b) in the FT-VI treated MSCs mice. Furthermore, when short-term survival was compared among the subgroups, unfucosylated MSCs did not significantly improve short-term survival over PBMNCs group (P=0.3) (Fig. 2a). However, FT-VI treated MSCs mice showed a significantly longer short-term survival compared to PBMNCs group (P=0.002) (Fig. 2b) and untreated MSCs mice (P=0.02) (Fig. 2c). CONCLUSION. Our data suggest that fucosylated MSCs exert a better anti-GVHD effect at a similar dose than unfucosylated MSCs. Additional data is being generated to confirm these preliminary results and optimize the dose and schedule of fucosylated MSCs. Disclosures No relevant conflicts of interest to declare.
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Gopakumar, Sricharan, Joy Gumin, Marc Daou, Daniel Ledbetter, Malcolm McDonald, Anwar Hossain, Shawn Hingtgen, Matthew Ewend, and Frederick Lang. "EXTH-62. STEM CELL DELIVERY OF ONCOLYTIC ADENOVIRUS DNX-2401 FOLLOWING SURGICAL RESECTION FOR THE TREATMENT OF GLIOBLASTOMA." Neuro-Oncology 21, Supplement_6 (November 2019): vi95. http://dx.doi.org/10.1093/neuonc/noz175.392.
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Abstract BACKGROUND The oncolytic virus DNX-2401 (Delta-24-RGD) is a novel treatment of GBM. While prior studies have examined intratumoral injection of DNX-2401 into recurrent GBM, the potential of delivering DNX-2401 into the surgical resection cavity using tumor-tropic human mesenchymal stem cells (MSCs) has not been evaluated. We hypothesize that exploiting a fibrin-based scaffold for transplanting MSCs loaded with DNX-2401 (MSCs-DNX-2401) into the resection cavity will improve viral delivery, decrease GBM recurrence, and extend overall survival. METHODS MSCs-DNX-2401 were seeded in a fibrin matrix or suspended in PBS and placed in the upper wells of transwell plates with U87 cells placed below. After one week, U87 cells were counted to compare rates of cellular killing and confirm release of DNX-2401 from fibrin-seeded MSCs. U87 cells were transduced with mCherry-Luciferase and implanted into the brains of athymic mice (N=16). After fluorescence-guided surgical resection of glioma xenografts, MSCs (control) or MSCs-DNX-2401 were delivered in the resection cavity using a fibrin scaffold. Serial bioluminescence imaging (BLI) was used to monitor tumor recurrence. RESULTS In transwell experiments, MSCs-DNX-2401 seeded in fibrin were as effective as MSCs-DNX-2401 without the scaffold, indicating that fibrin did not negatively impact cell viability or viral release. In in vivo studies mimicking residual tumor after surgical resection, treatment of the post-resection cavity with MSCs-DNX-2401 suspended in fibrin permitted retention of MSCs-DNX-2401 within the tumor bed. Kaplan-Meier survival analyses revealed statistically significant improved survival after treatment with MSC-DNX-2401 in fibrin compared to controls with 50% of animals demonstrating complete responses according to BLI (p < 0.05). CONCLUSION Delivering DNX-2401 into the post-resection surgical cavity using MSCs seeded in fibrin is capable of eradicating residual GBM and prolonging overall survival. These studies support the clinical translation of this approach in newly diagnosed patients undergoing surgical resection of GBM.
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Hajkova, Michaela, Filip Jaburek, Bianka Porubska, Pavla Bohacova, Vladimir Holan, and Magdalena Krulova. "Cyclosporine A promotes the therapeutic effect of mesenchymal stem cells on transplantation reaction." Clinical Science 133, no. 21 (November 2019): 2143–57. http://dx.doi.org/10.1042/cs20190294.
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Abstract The successful application of mesenchymal stem cells (MSCs) remains a major challenge in stem cell therapy. Currently, several in vitro studies have indicated potentially beneficial interactions of MSCs with immunosuppressive drugs. These interactions can be even more complex in vivo, and it is in this setting that we investigate the effect of MSCs in combination with Cyclosporine A (CsA) on transplantation reaction and allogeneic cell survival. Using an in vivo mouse model, we found that CsA significantly promoted the survival of MSCs in various organs and tissues of the recipients. In addition, compared to treatment with CsA or MSCs alone, the survival of transplanted allogeneic cells was significantly improved after the combined application of MSCs with CsA. We further observed that the combinatory treatment suppressed immune response to the alloantigen challenge and modulated the immune balance by harnessing proinflammatory CD4+T-bet+ and CD4+RORγt+ cell subsets. These changes were accompanied by a significant decrease in IL-17 production along with an elevated level of IL-10. Co-cultivation of purified naive CD4+ cells with peritoneal macrophages isolated from mice treated with MSCs and CsA revealed that MSC-educated macrophages play an important role in the immunomodulatory effect observed on distinct T-cell subpopulations. Taken together, our findings suggest that CsA promotes MSC survival in vivo and that the therapeutic efficacy of the combination of MSCs with CsA is superior to each monotherapy. This combinatory treatment thus represents a promising approach to reducing immunosuppressant dosage while maintaining or even improving the outcome of therapy.
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Moslem, Mohsen, Reto Eggenschwiler, Christian Wichmann, Raymund Buhmann, Tobias Cantz, and Reinhard Henschler. "Kindlin-2 Modulates the Survival, Differentiation, and Migration of Induced Pluripotent Cell-Derived Mesenchymal Stromal Cells." Stem Cells International 2017 (2017): 1–13. http://dx.doi.org/10.1155/2017/7316354.
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Kindlin-2 is a multidomain intracellular protein that can be recruited to β-integrin domains to activate signaling, initiate transcriptional programs, and bind to E-cadherin. To explore its involvement in cell fate decisions in mesenchymal cells, we studied the effects of Kindlin-2 modification (overexpression/knockdown) in induced pluripotent cell-derived mesenchymal stromal cells (iPSC-MSCs). Kindlin-2 overexpression resulted in increased proliferation and reduced apoptosis of iPSC-MSCs, as well as inhibition of their differentiation towards osteocytes, adipocytes, and chondrocytes. In contrast, siRNA-mediated Kindlin-2 knockdown induced increased apoptosis and increased differentiation response in iPSC-MSCs. The ability of iPSC-MSCs to adhere to VCAM-1/SDF-1α under shear stress and to migrate in a wound scratch assay was significantly increased after Kindlin-2 overexpression. In contrast, inhibition of mixed lymphocyte reaction (MLR) was generally independent of Kindlin-2 modulation in iPSC-MSCs, except for decreased production of interleukin-2 (IL-2) after Kindlin-2 overexpression in iPS-MSCs. Thus, Kindlin-2 upregulates survival, proliferation, stemness, and migration potential in iPSC-MSCs and may therefore be beneficial in optimizing performance of iPSC-MSC in therapies.
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Tan, Guangxiao, Dongmei He, and Gexiu Liu. "Mesenchymal Stem Cells Promoted Long-Term Graft Survival of Xenogenic Mouse Islet Cells in Recipient Mice." Blood 110, no. 11 (November 16, 2007): 612. http://dx.doi.org/10.1182/blood.v110.11.612.612.
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Abstract INTRODUCTION: In clinical islet transplantation, immunologic rejection is a major factor contributing to the poor engraftment of the islets. More recently, experimental evidence and preliminary clinical studies have demonstrated that mesenchymal stem cells (MSCs) have an important immune modulatory function. Here we described that co-transplantation of islet cells and donor MSCs from Balb/c mice promoted long-term graft survival of transplanted islet cells in recipient mice with diabetes. METHODS: Bone marrow MSCs of adult Balb/c mice were cultured, and characterized by surface molecules, the typical spindle-shaped morphology, and the ability of differentiation, and islet cells were isolated by the collagenase digestion method. After MSCs (10 5 ) were transplanted via the tail vein into C57BL/6 recipient mice with diabetes induced by streptozotocin, mixed MSCs and islet cells (1000:500) were injected under the kidney capsules. To assess whether MSCs downregulated T- cell responses in vivo, the histological examination by light microscape was performed, and status of blood T-lymphocytes by flow cytometry and immunofluorescence. Before and after transplantation, blood insulin and glucose levels were monitored. RESULTS: 7 days after transplantation, blood insulin and glucose levels in recipient mice injected with both islet cells and donor MSCs were (30.6±5.1)U/L and (6.9±0.4)mmol/L, respectively, whereas those in mice injected with islet cells alone were (19.8±4.9)U/L and (9.9±0.6)mmol/L, respectively. Moreover, Flow cytometry showed that expression of the activation markers CD25, CD69, and IFN-γ on CD4 or CD8 T cells increased significantly in latter. 6 wk after transplantation, blood insulin and glucose levels in the former still were normal, but not in latter. The histological examination showed that there was inflammation in latter, but not any morphological destructed evidence in former. The hormone release from islet cells-MSCs mixed grafts was a complete functional recovery. CONCLUSION: Our results indicated that MSCs suppressed allogeneic T- cell responses in vivo, and MSCs promoted long-term graft survival of transplanted islet cells in recipient mice with diabetes.
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Lee, Seahyoung, Eunhyun Choi, Min-Ji Cha, and Ki-Chul Hwang. "Cell Adhesion and Long-Term Survival of Transplanted Mesenchymal Stem Cells: A Prerequisite for Cell Therapy." Oxidative Medicine and Cellular Longevity 2015 (2015): 1–9. http://dx.doi.org/10.1155/2015/632902.
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The literature provides abundant evidence that mesenchymal stem cells (MSCs) are an attractive resource for therapeutics and have beneficial effects in regenerating injured tissues due to their self-renewal ability and broad differentiation potential. Although the therapeutic potential of MSCs has been proven in both preclinical and clinical studies, several questions have not yet been addressed. A major limitation to the use of MSCs in clinical applications is their poor viability at the site of injury due to the harsh microenvironment and to anoikis driven by the loss of cell adhesion. To improve the survival of the transplanted MSCs, strategies to regulate apoptotic signaling and enhance cell adhesion have been developed, such as pretreatment with cytokines, growth factors, and antiapoptotic molecules, genetic modifications, and hypoxic preconditioning. More appropriate animal models and a greater understanding of the therapeutic mechanisms of MSCs will be required for their successful clinical application. Nevertheless, the development of stem cell therapies using MSCs has the potential to treat degenerative diseases. This review discusses various approaches to improving MSC survival by inhibiting anoikis.
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Kim, Hawk, Sook-Kyoung Heo, Eui-Kyu Noh, Gi-Dong Gwon, Jae-Cheol Jo, Yunsuk Choi, and Jinny Park. "LIGHT (TNFSF14) Increases Survival and Proliferation of Human Bone Marrow-Derived Mesenchymal Stem Cells Via LTβR." Blood 128, no. 22 (December 2, 2016): 4546. http://dx.doi.org/10.1182/blood.v128.22.4546.4546.
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Abstract Background: LIGHT (Homologous to lymphotoxins, shows inducible expression, and competes with herpes simplex virus glycoprotein D for herpes virus entry mediator (HVEM)/tumor necrosis factor (TNF)-related 2, HVEM-L, TNFSF14, or CD258) is a member of TNF superfamily. It is expressed as a homotrimer on activated T cells and also on immune dendritic cells, and has three receptors such as HVEM, LT-¥â receptor (LT-¥âR) and decoy receptor 3 (DcR3). So far, three receptors with distinct cellular expression patterns are described to interact with LIGHT. Follicular DCs and stromal cells bind LIGHT through LT-¥âR. We monitored the effects of LIGHT on human bone marrow-derived mesenchymal stem cells (BM-MSCs). Methods: At first, we checked negative and positive differentiation markers of BM-MSCs. After rhLIGHT treatment, we monitored cell count, viability, proliferation, and cell cycle distribution. Also, PDGF and TGF¥â production by rhLIGHT were examined by ELISA, and biological mechanism were checked by immunoblotting through the rhLIGHT treatment. Results: FACS analysis result showed that LT-¥âR receptor is expressed in human BM-MSCs, but not HVEM indicating that LIGHT binds only LT-¥âR in human BM-MSCs. (Fig. 1A/B). rhLIGHT and LT-¥âR interaction increased cell numbers in BM-MSCs using an inverted microscope for cell number changes. Cell numbers by rhLIGHT enhanced dose-dependently and time-dependently (Fig. 2 A/B). Cell viability and the expression of p-AKT, Bcl-2 and Bcl-xL by rhLIGHT were significantly increased in BM-MSCs and rhLIGHT-induced IkB-¥á degradation activated NF-kB signal (Fig. 3A/B). rhLIGHT increased cell proliferation by increasing S/G2/M phase in BM-MSCs (Fig. 3C and 4D). And cell cycle regulatory proteins were enhanced by rhLIGHT in BM-MSC including cyclin B1, D1, D3, E, and cyclin dependent kinase (CDK) 1 and 2 while CDK inhibitor, p27 was decreased by rhLIGHT treatment (Fig. 3E). Moreover, rhLIGHT-induced PDGF and TGF¥â production by STAT3 and smad3 activation accelerated BM-MSCs proliferation. And we also confirmed differentiation potential of rhLIGHT on BM-MSCs by the staining for adipogenesis (Oil Red O staining), chondrogenesis (Alcian blue staining) and Osteogenesis (Alizarin red Staining). Conclusion: LIGHT and LT-¥âR interaction increases survival and proliferation of human BM-MSCs by activation of survival proteins, anti-apoptotic proteins, CDKs and cyclins. Moreover, LIGHT-induced STAT-3 and smad-3 activation causes PDGF and TGF-¥â production, and they enhance LIGHT signals in human BM-MSCs. We proposed the pathway of LIGHT and LT-¥âR interaction in human BM-MSCs. Therefore, LIGHT may play an important role for therapy of stem cells, and contribute to modification of MSCs. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures No relevant conflicts of interest to declare.
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Shahror, Rami Ahmad, Chung-Che Wu, Yung-Hsiao Chiang, and Kai-Yun Chen. "Genetically Modified Mesenchymal Stem Cells: The Next Generation of Stem Cell-Based Therapy for TBI." International Journal of Molecular Sciences 21, no. 11 (June 5, 2020): 4051. http://dx.doi.org/10.3390/ijms21114051.
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Mesenchymal stem cells (MSCs) are emerging as an attractive approach for restorative medicine in central nervous system (CNS) diseases and injuries, such as traumatic brain injury (TBI), due to their relatively easy derivation and therapeutic effect following transplantation. However, the long-term survival of the grafted cells and therapeutic efficacy need improvement. Here, we review the recent application of MSCs in TBI treatment in preclinical models. We discuss the genetic modification approaches designed to enhance the therapeutic potency of MSCs for TBI treatment by improving their survival after transplantation, enhancing their homing abilities and overexpressing neuroprotective and neuroregenerative factors. We highlight the latest preclinical studies that have used genetically modified MSCs for TBI treatment. The recent developments in MSCs’ biology and potential TBI therapeutic targets may sufficiently improve the genetic modification strategies for MSCs, potentially bringing effective MSC-based therapies for TBI treatment in humans.
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Wang, Ximei, and Yang Yuejin. "SITAGLIPTIN INCREASES survival OF MSCS IN HYPOXIA BY SUPPRESSING EXCESSIVE AUTOPHAGY." Journal of the American College of Cardiology 61, no. 10 (March 2013): E215. http://dx.doi.org/10.1016/s0735-1097(13)60216-8.
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Britt, Madolyn, Kristen Ramsey, Joseph Maramba, Blake Ushijima, Elissa Moller, Andriy Anishkin, Claudia Hase, and Sergei I. Sukharev. "MSCS is a Critical Component for Osmotic Survival of Vibrio Cholerae." Biophysical Journal 118, no. 3 (February 2020): 251a. http://dx.doi.org/10.1016/j.bpj.2019.11.1469.
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Zhou, Lukun, Shuang Liu, Chuanyi M. Lu, Jianfeng Yao, Yuyan Shen, Xin Yang, Sizhou Feng, and Mingzhe Han. "Bone Marrow-Derived Mesenchymal Stem Cells Overexpressing Akt1 Protect Against ConA-Induced Liver Injury in Mice." Blood 124, no. 21 (December 6, 2014): 5805. http://dx.doi.org/10.1182/blood.v124.21.5805.5805.
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Abstract Liver injury associated with veno-occlusive disease and graft-versus-host disease (GVHD) is a frequent and severe complication of hematopoietic stem cell transplantation, and remains an important cause of transplant-related mortality. Bone marrow derived mesenchymal stem cells (MSCs) have been evaluated for the prevention and treatment of refractory GVHD. However, poor cell viability has limited the therapeutic capacity of mesenchymal stromal cell therapy in vivo. In this study, we genetically engineered C57BL/6 mouse bone marrow MSCs using ex vivo retroviral transduction to overexpress Akt1, a serine threonine kinase and pro-survival signal protein, and tested the hypothesis that Akt1-expressing MSCs (Akt1-MSCs) are more resistant to apoptosis and can ameliorate acute liver injury induced by concanavalin A (ConA) in BALB/c mice. Cell proliferation and apoptosis analyses showed that, under both regular culture and high concentration IFN-γ (100 ng/mL) stimulation conditions, Akt1-GFP-MSCs had proliferation and survival (anti-apoptotic) advantages with down-regulated apoptosis pathways, compared to control GFP-MSCs. Twenty-four hours after receiving lethal dose of ConA (40 mg/kg, intravenous) (N=10 each group), no mouse survived, with or without 1x106 Akt1-MSCs or GFP-MSCs administration (intravenous); however, 3 and 1 survived in the 5×106 Akt1-MSCs group and 5×106 GFP-MSCs groups, respectively. In subsequent sub-lethal dose ConA (20 mg/kg) experiments, compared to GFP-MSCs, mice received Akt1-MSCs administration had significantly lower serum AST, ALT, TNF-α and IFN-γ levels and less histopathological abnormalities. In addition, Akt1-MSCs treated mice had significantly higher serum concentrations of IL-10, vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF). In vivo imaging showed that, hepatic fluorescence signal in sub-lethal ConA+Akt1-MSCs group was significantly stronger than ConA+GFP-MSCs group on day 0, and persisted up to 14 days, whereas the signal in ConA+GFP-MSCs, Akt1-MSCs and GFP-MSCs groups was negligible on both day 7 and day 14. Thus, bone marrow derived MSCs genetically enhanced with Akt1 had survival advantage in vitro and in vivo, and have the potential to be a potent therapy for prevention and amelioration of GVHD-associated liver impairment. Further translational pre-clinical studies are ongoing to further determine the efficacy, dosage and timing of administration of Akt1-MSCs in animal models. Disclosures No relevant conflicts of interest to declare.
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Graham, Julia, Iazsmin Bauer Ventura, Chad A. Newton, Cathryn Lee, Noelle Boctor, Janelle Vu Pugashetti, Claire Cutting, et al. "Myositis-specific antibodies identify a distinct interstitial pneumonia with autoimmune features phenotype." European Respiratory Journal 56, no. 6 (July 16, 2020): 2001205. http://dx.doi.org/10.1183/13993003.01205-2020.
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Interstitial pneumonia with autoimmune features (IPAF) characterises individuals with interstitial lung disease (ILD) and features of connective tissue disease (CTD) who fail to satisfy CTD criteria. Inclusion of myositis-specific antibodies (MSAs) in the IPAF criteria has generated controversy, as these patients also meet proposed criteria for an antisynthetase syndrome. Whether MSAs and myositis-associated antibodies (MAA) identify phenotypically distinct IPAF subgroups remains unclear.A multicentre, retrospective investigation was conducted to assess clinical features and outcomes in patients meeting IPAF criteria stratified by the presence of MSAs and MAAs. IPAF subgroups were compared to cohorts of patients with idiopathic inflammatory myopathy-ILD (IIM-ILD), idiopathic pulmonary fibrosis and non-IIM CTD-ILDs. The primary end-point assessed was 3-year transplant-free survival.269 patients met IPAF criteria, including 35 (13%) with MSAs and 65 (24.2%) with MAAs. Survival was highest among patients with IPAF-MSA and closely approximated those with IIM-ILD. Survival did not differ between IPAF-MAA and IPAF without MSA/MAA cohorts. Usual interstitial pneumonia (UIP) morphology was associated with differential outcome risk, with IPAF patients with non-UIP morphology approximating survival observed in non-IIM CTD-ILDs. MSAs, but not MAAs identified a unique IPAF phenotype characterised by clinical features and outcomes similar to IIM-ILD. UIP morphology was a strong predictor of outcome in others meeting IPAF criteria.Because IPAF is a research classification without clear treatment approach, these findings suggest that MSAs should be removed from the IPAF criteria and such patients should be managed as an IIM-ILD.
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Entin, Igor, Damir Herman, David R. Williams, John Freeman, John D. Shaughnessy, Bart Barlogie, and Joshua Epstein. "Myeloma Cell Interaction with Mesenchymal Stem Cells: Heterogeneity of Myeloma Cell Survival and Gene Expression Studies." Blood 112, no. 11 (November 16, 2008): 2738. http://dx.doi.org/10.1182/blood.v112.11.2738.2738.
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Abstract Myeloma is intimately associated with osteolytic bone disease, in part by inhibiting mesenchymal stem cell (MSC) differentiation into osteoblasts via blocking Wnt signaling (Tian, N Engl J Med2003;349:2483). Stimulation of osteoblast activity by bortezomib is associated with anti myeloma effects in patients (Zangari, Br J Haematol2005;131:71) and by MSC infusion in a model system (Yaccoby, Haematologica2006;91:192). To further evaluate the potential therapeutic utility of MSCs, we investigated the effects of MSCs on myeloma cell survival and the genomic consequences of MSC-myeloma cell interactions. CD138-purified myeloma (MM) cells from 16 consented patients were cocultured with MSCs derived from the bone marrow of 3 healthy donors (MSC 1, 2, &3, provided by Dr. D. Prockop, Tulane University). In 7 co-culture experiments, MSCs supported MM cell survival for 6–8 days compared to MM cells cultured alone, with a median viable cell count increasing by 2.3 fold v controls (1.2–4.1, p=0.003); in 4, coculture suppressed MM survival (median=0.5, range 0.3–0.7, p=0.016); and in 5 there was no effect (median=0.9, range 0.9–1.0). In 3 experiments, the effects of the different MSCs on MM cell survival varied inconsistently among the 3 MSCs, from 0.5 to 2.5 fold surviving cells. In order to understand this heterogeneity, we investigated the genomic consequences of MM-MSC interactions. RNA was extracted immediately after mixing (t=0) and following 18 hours co-culture (t=18), and changes in gene expression analyzed using the Affymetrix microarray system. Since myeloma cells adhere tightly to MSCs, we analyzed expression changes in 1,708 genes expressed only in MM cells and 4862 expressed only in MSCs. At t=18, 250 MM cell genes were changed by >2 fold compared with t=0 (222 up and 28 down regulated), and 1,036 MSC genes were changed >2 fold (1018 up and 18 downregulated). Each of the 3 MSCs also had unique genes expressed (40, 85 and 162 for MSC 1, 2, &3, respectively), of which expression of 12, 30, and 39, respectively, was changed by >2 fold. Analysis of 776 MM- and 2398 MSC-related genes after a signal cutoff of 500 with Ingenuity Pathways Analysis software showed changes in the expression of several groups of interrelated genes following co-culture. For MM, these included ERKs, AKT, NFKB, E2F1, and FOS. The transcription regulators BTG2, ACTN2, CALR, E2F1, E2F5, and ATF7 were up regulated, while FOS and FOXM1 were down regulated. Groups changed in MSCs included IL1B, CCND1, MYC, CTBP1, EGFR, RUNX1, HRAS, and SMAD3. There were minor differences in changes of the expression patterns of some of the probesets between the three MSCs, likely related to alternative splicing or to variations in the 3′-UTR. These studies continue in order to discern possible differences in the interactions between MM cells and MSCs, and to identify whether MM cells or MSC determine the outcome of these differences.
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Strohschein, K., P. Radojewski, T. Winkler, G. N. Duda, C. Perka, and P. von Roth. "In Vivo Bioluminescence Imaging – A Suitable Method to Track Mesenchymal Stromal Cells in a Skeletal Muscle Trauma§." Open Orthopaedics Journal 9, no. 1 (July 31, 2015): 262–69. http://dx.doi.org/10.2174/1874325001509010262.
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Cell-based therapies have emerged during the last decade in various clinical fields. Especially mesenchymal stromal cells (MSCs) have been used in pre-clinical and clinical applications in cardiovascular, neurodegenerative and musculoskeletal disorders. In order to validate survival and viability as well as possible engraftment of MSCs into the host tissue a live cell imaging technique is needed that allows non-invasive, temporal imaging of cellular kinetics as well as evaluation of cell viability after transplantation. In this study we used luciferase-based bioluminescence imaging (BLI) to investigate the survival of autologous MSCs transplanted into a severely crushed soleus muscle of the rats. Furthermore we compared local as well as intra-arterial (i.a.) administration of cells and analyzed if luciferase transduced MSCs depict the same characteristics in vitro as non-transduced MSCs. We could show that transduction of MSCs does not alter their in vitro characteristics, thus, transduced MSCs display the same differentiation, proliferation and migration capacity as non-transduced cells. Using BLI we could track MSCs transplanted into a crushed soleus muscle until day 7 irrespective of local or i.a. application. Hence, our study proves that luciferase-based BLI is a suitable method for in vivo tracking of MSCs in skeletal muscle trauma in rats.
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Oliveira, Régis Linhares, Pedro Cesar Chagastelles, Patrícia Sesterheim, and Patricia Pranke. "In Vivo Immunogenic Response to Allogeneic Mesenchymal Stem Cells and the Role of Preactivated Mesenchymal Stem Cells Cotransplanted with Allogeneic Islets." Stem Cells International 2017 (2017): 1–12. http://dx.doi.org/10.1155/2017/9824698.
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Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiating into cells from the mesenchymal lineage. The hypoimmunogenic characteristic of MSCs has encouraged studies using allogeneic MSCs for the treatment of autoimmune diseases and inflammatory conditions. Promising preclinical results and the safety of allogeneic MSC transplantation have created the possibility of “off-the-shelf” clinical application of allogeneic cells. This study has aimed to evaluate the survival of untreated and IFN-γ- and TNF-α-treated (preactivated) allogeneic MSCs transplanted under the kidney capsule of immunocompetent mice together with the role of preactivated MSCs after cotransplantation with allogeneic islets. The preactivation of MSCs upregulated the gene expression of anti-inflammatory molecules and also enhanced their immunomodulatory capacity in vitro. In vivo, allogeneic MSCs provoked an immunogenic response, with the infiltration of inflammatory cells at the transplant site and full graft rejection in both the untreated and preactivated groups. Allogeneic islets cotransplanted with preactivated MSCs prolonged graft survival for about 6 days, compared with islet alone. The present results corroborate the hypothesis that allogeneic MSCs are not immune-privileged and that after playing their therapeutic role they are rejected. Strategies that reduce allogeneic MSC immunogenicity can potentially prolong their in vivo persistence and improve the therapeutic effects.
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Kim, Jin Hyun, Dong Jun Park, Ji Chul Yun, Myeong Hee Jung, Hee Dong Yeo, Hyun-Jung Kim, Dong Wook Kim, et al. "Human adipose tissue-derived mesenchymal stem cells protect kidneys from cisplatin nephrotoxicity in rats." American Journal of Physiology-Renal Physiology 302, no. 9 (May 1, 2012): F1141—F1150. http://dx.doi.org/10.1152/ajprenal.00060.2011.
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Cisplatin has multiple cellular targets and modes of action that lead to nephrotoxicity. This suggests novel therapies that act at multiple cisplatin target sites may be effective. We tested whether human adipose tissue-derived mesenchymal stem cells (Ad-MSCs) can affect multiple target sites and protect against cisplatin-induced kidney damage. Rats were divided into four groups: control, infused with Ad-MSCs, injected with cisplatin, and cisplatin followed by infusion of Ad-MSCs. Animal survival and renal function were decreased and histological damage was increased in cisplatin-treated rats at day 3. Infusion of Ad-MSCs ameliorated renal dysfunction and tissue injury caused by cisplatin, leading to increased survival. Apoptotic cell death in the kidney was significantly reduced by infusion of Ad-MSCs. Activation of p53, JNK, and ERK and the expression of inflammation-related molecules were also decreased in the kidney that received Ad-MSCs. Very few Ad-MSCs were detected in the kidney. Conditioned medium from cultured Ad-MSCs had renal-protective functions in vivo and in vitro. Renal dysfunction and tissue damage caused by cisplatin were significantly reduced in rats treated with Ad-MSCs-conditioned medium. The viability of cultured renal proximal tubular cells exposed to cisplatin was also improved by coculture with Ad-MSCs or with conditioned medium. Release of proinflammatory mediators induced by cisplatin was inhibited in coculture with Ad-MSCs. Our results show that human Ad-MSCs exert a paracrine-protective effect on cisplatin nephrotoxicity at multiple target sites and suggest that human Ad-MSCs might be a new therapeutic approach for patients with acute kidney injury.
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Fontein, Duveken B. Y., Caroline Seynaeve, Peyman Hadji, Elysée T. M. Hille, Willemien van de Water, Hein Putter, Elma Meershoek-Klein Kranenbarg, et al. "Specific Adverse Events Predict Survival Benefit in Patients Treated With Tamoxifen or Aromatase Inhibitors: An International Tamoxifen Exemestane Adjuvant Multinational Trial Analysis." Journal of Clinical Oncology 31, no. 18 (June 20, 2013): 2257–64. http://dx.doi.org/10.1200/jco.2012.45.3068.
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Purpose Specific adverse events (AEs) associated with endocrine therapy and related to depletion or blocking of circulating estrogens may be related to treatment efficacy. We investigated the relationship between survival outcomes and specific AEs including vasomotor symptoms (VMSs), musculoskeletal adverse events (MSAEs), and vulvovaginal symptoms (VVSs) in postmenopausal patients with breast cancer participating in the international Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. Patients and Methods Primary efficacy end points were disease-free survival (DFS), overall survival (OS), and distant metastases (DM). VMSs, MSAEs, and VVSs arising in the first year of endocrine treatment were considered. Patients who did not start or who discontinued their allocated therapy and/or had an event (recurrence/death) within 1 year after randomization were excluded. Landmark analyses and time-dependent multivariate Cox proportional hazards models assessed survival differences up to 5 years from the start of treatment. Results A total of 9,325 patients were included. Patients with specific AEs (v nonspecific or no AEs) had better DFS and OS (multivariate hazard ratio [HR] for DFS: VMSs, 0.731 [95% CI, 0.618 to 0.866]; MSAEs, 0.826 [95% CI, 0.694 to 0.982]; VVSs, 0.769 [95% CI, 0.585 to 1.01]; multivariate HR for OS: VMSs, 0.583 [95% CI, 0.424 to 0.803]; MSAEs, 0.811 [95% CI, 0.654 to 1.005]; VVSs, 0.570 [95% CI, 0.391 to 0.831]) and fewer DM (VMSs, 0.813 [95% CI, 0.664 to 0.996]; MSAEs, 0.749 [95% CI, 0.601 to 0.934]; VVSs, 0.687 [95% CI, 0.436 to 1.085]) than patients not reporting these symptoms. Increasing numbers of specific AEs were also associated with better survival outcomes. Outcomes were unrelated to treatment allocation. Conclusion Certain specific AEs are associated with superior survival outcomes and may therefore be useful in predicting treatment responses in patients with breast cancer treated with endocrine therapy.
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Sim, Woo-Sup, Bong-Woo Park, Kiwon Ban, and Hun-Jun Park. "In Situ Preconditioning of Human Mesenchymal Stem Cells Elicits Comprehensive Cardiac Repair Following Myocardial Infarction." International Journal of Molecular Sciences 22, no. 3 (February 1, 2021): 1449. http://dx.doi.org/10.3390/ijms22031449.
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Human bone marrow-derived mesenchymal stem cells (BM-MSCs), represented as a population of adult stem cells, have long been considered as one of the most promising sources for cell-based cardiac regenerative therapy. However, their clinical use has been significantly hampered by low survival and poor retention following administration into failing hearts. Here, to improve the therapeutic effectiveness of BM-MSCs, we examined a novel therapeutic platform named in situ preconditioning in a rat myocardial infarction (MI) model. In situ preconditioning was induced by a combinatory treatment of BM-MSCs with genetically engineered hepatocyte growth factor-expressing MSCs (HGF-eMSCs) and heart-derived extracellular matrix (hdECM) hydrogel. Subsequently, our results demonstrated that in situ preconditioning with cell mixture substantially improved the survival/retention of BM-MSCs in the MI-induced rat hearts. Enhanced retention of BM-MSCs ultimately led to a significant cardiac function improvement, which was derived from the protection of myocardium and enhancement of vessel formation in the MI hearts. The results provide compelling evidence that in situ preconditioning devised to improve the therapeutic potential of BM-MSCs can be an effective strategy to achieve cardiac repair of MI hearts.
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Xue, Xiaodong, Yu Liu, Jian Zhang, Tao Liu, Zhonglu Yang, and Huishan Wang. "Bcl-xL Genetic Modification Enhanced the Therapeutic Efficacy of Mesenchymal Stem Cell Transplantation in the Treatment of Heart Infarction." Stem Cells International 2015 (2015): 1–14. http://dx.doi.org/10.1155/2015/176409.
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Objectives.Low survival rate of mesenchymal stem cells (MSCs) severely limited the therapeutic efficacy of cell therapy in the treatment of myocardial infarction (MI). Bcl-xL genetic modification might enhance MSC survival after transplantation.Methods.Adult rat bone marrow MSCs were modified with human Bcl-xL gene (hBcl-xL-MSCs) or empty vector (vector-MSCs). MSC apoptosis and paracrine secretions were characterized using flow cytometry, TUNEL, and ELISAin vitro.In vivo, randomized adult rats with MI received myocardial injections of one of the three reagents: hBcl-xL-MSCs, vector-MSCs, or culture medium. Histochemistry, TUNEL, and echocardiography were carried out to evaluate cell engraftment, apoptosis, angiogenesis, scar formation, and cardiac functional recovery.Results.In vitro, cell apoptosis decreased 43%, and vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1), and plate-derived growth factor (PDGF) increased 1.5-, 0.7-, and 1.2-fold, respectively, in hBcl-xL-MSCs versus wild type and vector-MSCs.In vivo, cell apoptosis decreased 40% and 26% in hBcl-xL-MSC group versus medium and vector-MSC group, respectively. Similar results were observed in cell engraftment, angiogenesis, scar formation, and cardiac functional recovery.Conclusions.Genetic modification of MSCs with hBcl-xL gene could be an intriguing strategy to improve the therapeutic efficacy of cell therapy in the treatment of heart infarction.
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Takam Kamga, Paul, Bassi Giulio, Adriana Cassaro, Roberta Stradoni, Martina Midolo, Omar Perbellini, and Mauro Krampera. "Role of Stromal Cell-Mediated Notch Signaling in AML Resistance to Chemotherapy." Blood 124, no. 21 (December 6, 2014): 1044. http://dx.doi.org/10.1182/blood.v124.21.1044.1044.
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Abstract Introduction: Our group has recently shown that bone marrow-mesenchymal stromal cell (BM-MSCs)-mediated Notch signaling may control survival and chemoresistance of B-acute lymphoblastic leukemia (B-ALL) and chronic lymphocytic leukemia (CLL) cells. Conversely, the role of Notch signaling in acute myeloid leukemia (AML) remains controversial, as its contribution to the crosstalk between BM-MSCs and AML cells is still unknown. Thus, we evaluated the role of the Notch pathway in the proliferation, survival and chemoresistance of AML primary blast cells in co-culture with BM-MSCs. Methods: AML blast cells were obtained after informed consent from bone marrow samples (30) and peripheral blood (20) of AML patients, according to the Institutional guidelines. BM-MSCs were expanded from bone marrow of 12 healthy donors (BM-MSCs) and of 12 AML-patients (BM-MSCs*). PCR, FACS analysis and western immunoblotting were used to study the expression of Notch receptors and ligands, as well as Notch activation status, in AML cells and BM-MSCs. AML cells were co-cultured with BM-MSCs or BM-MSCs* at 10:1 (AML:BM-MSCs) ratio for 2 to 3 days in presence of Cytarabine, Etoposide, Idarubicin, as well as in presence or absence of anti-Notch-1, -2, -3, -4, anti-Jagged1, -2 and anti-DLL3 blocking antibodies or gamma secretase inhibitor-XII (GSI-XII). Cell viability was evaluated by Annexin-V/Propidium Iodide (PI) and MTT; proliferation and cell cycle were assessed through CFSE dilution and PI methods, respectively. Results: AML cells expressed Notch receptors and ligands, showing Notch-1, -2, Jagged-1, -2 and DLL-3 signature, while BM-MSCs/ BM-MSCs* showed expression of Notch-1, -2, -3, -4 and Jagged-1, -2 and DLL-1. We then analyzed Notch activation in different cell types by evaluating the expression of NICD-1, -2, -3 as well as Hes-1. We found that at least 50% of AML samples showed basal Notch activation while BM-MSCs/ BM-MSCs* showed slight Notch activation. The expression and activation pattern were modulated after 3 days of co-culture with either BM-MSCs or BM-MSCs*. The pan blockade of Notch signaling by GSI-XII were capable to inhibit AML cell proliferation as well as induce AML cell apoptosis in culture or in co-culture with BM-MSCs/ BM-MSCs*. The addition of chemotherapeutic agents decreased AML cell viability in culture, while a significant rescue from apoptosis was observed when cocultured with BM-MSCs or BM-MSCs*. Pan Notch signaling blockade by either GSI-XII or combination of Notch receptor-blocking antibodies in presence of chemotherapeutic agents significantly lowered the supportive role of BM-MSCs towards AML cell lines. The specific blockade of Notch-1, -2, -3 or Jagged-1, -2 rescued partially the chemosensibility, while blockade of Notch-4 or DLL-3 rescued totally the chemosensitivity of primary AML cells in co-culture with BM-MSCs. Conclusions: These results suggest that Notch signaling may represent a potential therapeutic strategy to overcome bone marrow stromal-mediated survival and chemoresistance of AML. Moreover Notch blocking antibodies were able to impair the survival benefit imparted by bone marrow stromal cells. Therefore blocking Notch antibodies could be a useful strategy to improve the efficiency of AML chemotherapy. Disclosures No relevant conflicts of interest to declare.
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Tabe, Yoko, Linhua Jin, Yasuhito Hatanaka, Saiko Kazuno, Tsutomu Fujimura, Hiromichi Matsushita, Takashi Ueno, Keisuke Sasai, and Takashi Miida. "Low Dose-Radiation of Bone Marrow Stromal Cells Supports Pre-Leukemic Cell Survival Via Adhesion and Inflammatory Signaling Stimulation." Blood 120, no. 21 (November 16, 2012): 4610. http://dx.doi.org/10.1182/blood.v120.21.4610.4610.
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Abstract Abstract 4610 Low-dose irradiation (LDI) exposure is a form of environmental carcinogen, which is of significant interest after the nuclear accident in Japan. In this study, we investigated the LDI-induced molecular alterations of bone marrow (BM) –derived stromal cells (MSCs), and the biological response of pre-leukemic cells neighbor to LDI exposed MSCs. As the model of pre-leukemic cells, we utilized the Epstein- Barr virus (EBV) infected and immortalized B lymphocyte cell line (EBV-B). In MSCs, exposed to 100 mGy irradiation (4MVX rayfrom a LINAC) caused cell growth inhibition (75.8±2.4 % of control, p<0.001, MTT assay) with moderate apoptosis induction (SubG1 %; control 2.3±0.4, radiation 7.3±2.3, p=0.03, PI cell cycle analysis) at 24 hrs. Screening up to 28,869 genes by cDNA microarray (Human Gene 1.0 ST Array, Affymetrix) revealed 48 up-regulated and 45 down-regulated genes (>1.3 fold) in irradiated MSCs (at 24 hrs) compared to non-irradiated MSCs. The functional network analysis of cDNA microarray data by MetaCore (GeneGo) showed an enrichment of the adhesion/ECM remodeling pathways. TaqMan RT-PCR confirmed significant up-regulation of ECM scaffold Sulfatase1 mRNA (2.0±0.1 fold, p=0.004). Proteomic analysis utilized isobaric tags for relative and absolute quantitation (iTRAQ, Applied Biosystems), identified 32 up-regulated and 1 down-regulated proteins (p<0.05) among 1,536 detected proteins comparing irradiated MSCs (at 24 hrs) with non-irradiated MSCs. KEGGontology analysis (Kyoto University) found the activation of focal adhesion and apoptosis pathways in irradiated MSCs; among 32 up-regulated proteins, six are involoved in adhesion/cytoskeleton regulation (Prelamin-A; p<0.001, Catenin beta-1; p=0.03, Keratin type II; p=0.02, Collagen alpha1; p=0.02, alpha actinin1 and 4; p=0.01, p=0.02) and three are involved in apoptosis/senescence (Stress-70 protein l; p=0.02, Endoplasmin; p=0.008, Prohibitin; p=0.04). These changes were accompanied with increased secretion of inflammation and coagulation marker protein plasminogen activator inhibitor 1 (PAI-1) from irradiated MSCs (control 10.1±0.03 ng/mL, radiation >15.0 ng/mL, at 72hrs). We then investigated the effect of LDI exposed MSCs on EBV-B cell proliferation. Under low-serum growth condition (1% FBS), co-culture with pre-irradiated (100 mGy) MSC layers supported EBV-B cell proliferation more prominently than non-irradiated MSCs (118.3±4.0 % viable cell number, p<0.001, 72hrs). Gene expression profiles by cDNA microarray and sequenced MetaCore ontology revealed 53 up-regulated and 39 down-regulated genes showing an enrichment of the coagulation and cell adhesion pathways in EBV-B cells co-cultured with pre-irradiation of MSCs compared to the ones co-cultured with non-irradiated MSCs. Up-regulation of anti-apoptotic BCL2 mRNA (0.5±0.03 fold, p=0.02) and inflammatory IL8 mRNA (2.0±0.03 fold, p<0.001) was further detected by TaqMan RT-PCR. The purity of EBV-B cells separated from MSCs was confirmed by lack of CD90 mRNA expression by PCR. These data suggest that LDI exposure to MSCs leads to latent adhesion and inflammatory signaling in MSCs, which potentially activates pro-survival pathways of co-cultured pre-leukemic EBV-B cells. In summary, we present the biosignature of the response of BM-derived stromal cells to LDI utilizing gene array and quantitative proteomics analysis that may have important implications for risk assessment in environmental medicine. Disclosures: No relevant conflicts of interest to declare.
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Diniz, Ivana Márcia Alves, Adriana Bona Matos, and Márcia Martins Marques. "Laser Phototherapy Enhances Mesenchymal Stem Cells Survival in Response to the Dental Adhesives." Scientific World Journal 2015 (2015): 1–6. http://dx.doi.org/10.1155/2015/671789.
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Background. We investigated the influence of laser phototherapy (LPT) on the survival of human mesenchymal stem cells (MSCs) submitted to substances leached from dental adhesives.Method. MSCs were isolated and characterized. Oral mucosa fibroblasts and osteoblast-like cells were used as comparative controls. Cultured medium conditioned with two adhesive systems was applied to the cultures. Cell monolayers were exposed or not to LPT. Laser irradiations were performed using a red laser (GaAlAs, 780 nm, 0.04 cm2, 40 mW, 1 W/cm2, 0.4 J, 10 seconds, 1 point, 10 J/cm2). After 24 h, cell viability was assessed by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide reduction assay. Data were statistically compared by ANOVA followed by Tukey’s test (P<0.05).Results. Different cell types showed different viabilities in response to the same materials. Substances leached from adhesives were less cytotoxic to MSCs than to other cell types. Substances leached from Clearfil SE Bond were highly cytotoxic to all cell types tested, except to the MSCs when applied polymerized and in association with LPT. LPT was unable to significantly increase the cell viability of fibroblasts and osteoblast-like cells submitted to the dental adhesives.Conclusion. LPT enhances mesenchymal stem cells survival in response to substances leached from dental adhesives.
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Pham, Phuc Van, Tam Thanh Nguyen, Nhung Thi Hong Vuong, Tuyet Thi Bach Duong, and Ngoc Kim Phan. "INVESTIGATING COOLING RATE AND FETAL BOVINE SERUM CONCENTRATION ON SURVIVAL AND STEMNESS OF MESENCHYMAL STEM CELLS AFTER CRYOPRESERVATION." Science and Technology Development Journal 12, no. 9 (May 15, 2009): 12–22. http://dx.doi.org/10.32508/stdj.v12i9.2281.
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Mesenchymal stem cells (MSCs) can be derived from many different sources. Umbilical cord blood is a rich source of MSCs. The cryopreservation of MSCs that MSCs are still alive and differentiate into many different kinds of functional cells is very important. The aims of this research are to identify ratio of alive and dead cells as well as stemness of them after thaw. The results showed that the stemness was not affected by cryopreservative protocols or media. All cells being alive after thaw could form colonies and differentiate into adipocytes and osteoblasts. Ratio of alive and dead cells was affected very much by cryopreservative protocols and media.
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Mohsin, Sadia, Constantine D. Troupes, Timothy Starosta, Thomas E. Sharp, Elorm J. Agra, Shavonn Smith, Jason M. Duran, et al. "Unique Features of Cortical Bone Stem Cells Associated With Repair of the Injured Heart." Circulation Research 117, no. 12 (December 4, 2015): 1024–33. http://dx.doi.org/10.1161/circresaha.115.307362.
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Rationale: Adoptive transfer of multiple stem cell types has only had modest effects on the structure and function of failing human hearts. Despite increasing the use of stem cell therapies, consensus on the optimal stem cell type is not adequately defined. The modest cardiac repair and functional improvement in patients with cardiac disease warrants identification of a novel stem cell population that possesses properties that induce a more substantial improvement in patients with heart failure. Objective: To characterize and compare surface marker expression, proliferation, survival, migration, and differentiation capacity of cortical bone stem cells (CBSCs) relative to mesenchymal stem cells (MSCs) and cardiac-derived stem cells (CDCs), which have already been tested in early stage clinical trials. Methods and Results: CBSCs, MSCs, and CDCs were isolated from Gottingen miniswine or transgenic C57/BL6 mice expressing enhanced green fluorescent protein and were expanded in vitro. CBSCs possess a unique surface marker profile, including high expression of CD61 and integrin β4 versus CDCs and MSCs. In addition, CBSCs were morphologically distinct and showed enhanced proliferation capacity versus CDCs and MSCs. CBSCs had significantly better survival after exposure to an apoptotic stimuli when compared with MSCs. ATP and histamine induced a transient increase of intracellular Ca 2+ concentration in CBSCs versus CDCs and MSCs, which either respond to ATP or histamine only further documenting the differences between the 3 cell types. Conclusions: CBSCs are unique from CDCs and MSCs and possess enhanced proliferative, survival, and lineage commitment capacity that could account for the enhanced protective effects after cardiac injury.
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Ave, Elisa, Federica Frezzato, Cristina Gattazzo, Valentina Trimarco, Veronica Martini, Andrea Visentin, Monica Castelli, et al. "Increased Survival and Migration of CLL B-Cells in the Presence of Marrow Mesenchymal Stromal Cells: Novel Findings for Microenvironment-Targeted Therapies." Blood 120, no. 21 (November 16, 2012): 4571. http://dx.doi.org/10.1182/blood.v120.21.4571.4571.
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Abstract Abstract 4571 Background. The accumulation of CD19+/CD5+/CD23+ B cells with a prolonged lifespan in peripheral blood, secondary lymphoid organs and bone marrow (BM) is a peculiar feature of B-cell chronic lymphocytic leukemia (B-CLL). Since CLL cells removed from the in vivo microenvironment and in vitro cultured rapidly undergo spontaneous apoptosis, bidirectional interactions between malignant and by-stander cells may lead to an abnormal microenvironment that confers growth advantages to neoplastic clone. Mesenchymal Stromal Cells (MSCs) are the dominant marrow stromal population in indolent subtype of CLL/small lymphocytic leukemia (SLL) and follicular lymphoma (FL), rather than other aggressive B-cell lymphomas, and are involved in B-CLL cell survival. Despite the phenotypic and cytologic homogeneity, CLL is characterized by extremely variable clinical courses, suggesting that malignant B-cells hold variable degrees of dependency on pro-survival signals coming from the microenvironment. The aim of this study was to assess the role of MSCs in CLL B-cell localization and survival, defining the degree of dependency of leukemic B-cells from external pro-survival signals, with the ultimate goal of identifying patients that mostly benefit microenvironment-targeted therapies. Methods. MSCs isolated from the BM of 47 B-CLL patients were expanded ex vivo and characterized through flow cytometry analysis and differentiation cultures. Fresh isolated CLL peripheral blood mononuclear cells were co-cultured with CLL-MSCs or stromal cells and apoptosis were measured by Annexin V test and western blotting analysis (PARP-1 detection). Chemotactic assays were performed. Results. The survival of neoplastic cells ranged from 13.3% (±13.2) in leukemic cells cultured in medium alone to 58.5% (±17.2) when leukemic cells were cultured in presence of CLL-MSCs (p<0.01). Transwell experiments showed that the anti-apoptotic effect is mediated by soluble factors produced by MSCs. We investigated whether different CLL clones show a different susceptibility to spontaneous apoptosis when co-cultured in presence of MSCs recovered from B-CLL patients. The detection of the 85KDa cleaved PARP fragment in all CLL B-cells cultured in medium alone confirmed that they underwent spontaneous apoptosis. At the same time, the presence or the lacking of the cleaved fragment of PARP-1 on CLL B-cells after 7 day-co-cultures with MSCs discriminated patients into two groups: non-responder (89 kDa Parp fragment detectable) and responder (89 kDa Parp fragment not detectable) to microenvironment pro-survival signals. Finally, chemotaxis tests showed the ability of MSCs to produce and release molecules promoting the migration and the localization of neoplastic B-cells in bone marrow (Migration Index of leukemic cells: 5.1; Migration Index of normal B cells: 1.9; p<0.01). Conclusions. MSCs derived from patients with B-CLL provide survival signals to neoplastic cells, extending their lifespan and producing chemotactic factors that favour their accumulation into BM. On the other hand, CLL cells display heterogeneous responses to environmental pro-survival signals, suggesting that each CLL clone could differently react to the microenvironment protection. The blocking of the cross-talk between malignant clone and accessory cells within the microenvironment might represent an attractive novel strategy for CLL therapy. Our data provide the rationale for tailored therapies which powerfully target the cross-talk with marrow cells, particularly on patients carrying a clone more sensitive to anti-apoptotic signals coming from the microenvironment. Disclosures: No relevant conflicts of interest to declare.
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Wang, Lu, Shu Li, Han-Yu Wang, Juan Zeng, Zheng-Zheng Zhang, Dong-Yong Lv, and Wei-Hong Kuang. "In a Rat Model of Acute Liver Failure, Icaritin Improved the Therapeutic Effect of Mesenchymal Stem Cells by Activation of the Hepatocyte Growth Factor/c-Met Pathway." Evidence-Based Complementary and Alternative Medicine 2019 (November 7, 2019): 1–13. http://dx.doi.org/10.1155/2019/4253846.
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Acute liver failure (ALF) is a serious life-threatening condition. Mesenchymal stem cells (MSCs) may be an effective treatment for this condition and a good alternative to liver transplantation. Icaritin (ICT) is an active ingredient of the genus Epimedium, a traditional Chinese medicine, with the potential to enhance the proliferation of MSCs. The purpose of this study was to explore whether ICT increased the therapeutic effects of MSCs and explore its underlying mechanisms. For in vivo experiments, a rat ALF model was established by intraperitoneal injection of D(+)-galactosamine/ lipopolysaccharide. MSCs cocultured with ICT were used to treat ALF rats and the protective effects assessed as survival rate, levels of serum AST and ALT, and histological changes in liver tissue. For in vitro experiments, MSCs were treated in serum-free culture for 72 h to simulate the disruption of intrahepatic microcirculation. MSCs apoptosis was examined to determine whether ICT rescued impaired MSCs. The role of the hepatocyte growth factor (HGF)/c-Met pathway in MSCs was assessed by constructing genetically modified MSCs overexpressing c-Met and by using the c-Met receptor inhibitor (crizotinib). The results showed that MSCs increased the survival rate of ALF rats and reduced liver damage. MSCs cocultured with ICT exerted a greater therapeutic effect than MSCs alone. Further, the HGF/c-Met pathway played a key role in the antiapoptotic activity of MSCs, which was associated with the optimized efficacy of ICT. In conclusion, this study demonstrated that ICT enhances the therapeutic effect of MSCs in a model of ALF, improving the antiapoptotic potential of MSCs by upregulation of the HGF/c-Met pathway. The combination of stem cell therapy with traditional herbal extracts may improve MSC-based clinical applications.
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Copland, Ian B., Marc E. Jolicoeur, Marc-Antoine Gillis, Jessica Cuerquis, Nicoletta Eliopoulos, Borhane Annabi, Angelo Calderone, Jean-Francois Tanguay, Anique Ducharme, and Jacques Galipeau. "Erythropoietin (Epo) Secreting Mesenchymal Stromal Cells and Autocrine Signalling Via the Epo Receptor. A Novel, Cell-Based Paracrine Epo Delivery System for Cardiovascular Therapy." Blood 110, no. 11 (November 16, 2007): 1198. http://dx.doi.org/10.1182/blood.v110.11.1198.1198.
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Abstract Separately, the roles of MSCs and erythropoietin (Epo) in cardiovascular regenerative therapy have expanded rapidly. However, poor in vivo survival/engraftment of MSCs and Epo’s short half-life and bioavailability, limit their individual effectiveness. We propose that a combinatorial approach would be synergisitic. We therefore determined whether administration of Epo-secreting Mesenchymal stromal cells (MSCs) could represent a better therapeutic platform in cardiovascular medicine than MSCs in their primeval form. MSCs from C57Bl/6 mice were retrovirally transduced to express murine Epo (Epo+MSCs) and compared to wild type (WT) MSCs in relation to their abilities to promote positive heart tissue remodelling following myocardial infarction (MI). Relative to WT-MSCs, we found that via an Epo/EpoR autocrine loop, Epo+MSCs have an enhanced proliferative capacity and are more resilient to apoptotic stimuli. In vivo, Epo+MSCs also have enhanced survival and can initiate a more robust host-derived angiogenic response. Injection of WT-MSCs or Epo+MSCs into the borderzone of the MI following ligation of the left coronary artery demonstrated engraftment within the borderzone seven days post-implantation, while sequential (7 and 14 day post-MI) echocardiograms and invasive hemodynamic measurements (14 days post-MI) showed that the Epo+MSC group exhibited significantly improved LV systolic and diastolic function compared to WT-MSCs injected animals and PBS controls (Fractional shortening 29.7% ± 8.5 versus 19.9% ± 6.6 and 19.1% ± 7.4 respectively, p=0.02). Myocardial capillary density was significantly higher in the Epo+MSC group and was coupled to reduced neutrophilic infiltration by direct actions of Epo on endothelial and neutrophil chemotaxis. In conclusion, we show that Epo overexpression enhances the cellular regenerative properties of MSCs by both autocrine and paracrine pathways.