Tesis: "Angiogenic cells"

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A, Ahern Megan, Black Claudine P, Seedorf Gregory J, Baker Christopher D y Shepherd Douglas P. "Hyperoxia impairs pro-angiogenic RNA production in preterm endothelial colony-forming cells". AMER INST MATHEMATICAL SCIENCES-AIMS, 2017. http://hdl.handle.net/10150/626103.

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Disruptions in the response of endothelial progenitor cells to changes in oxygen environment may present a possible mechanism behind multiple pediatric pulmonary disease models, such as bronchopulmonary dysplasia. Using high-throughput fixed single-cell protein and RNA imaging, we have created "stop-motion" movies of Thymosin. 4 (T beta 4) and Hypoxia Inducible Factor 1 alpha (HIF-1 alpha) protein expression and vascular endothelial growth factor (vegf) and endothelial nitric oxide synthase (eNOS) mRNA in human umbilical cord-derived endothelial colony-forming cells (ECFC). ECFC were grown in vitro under both room air and hyperoxia (50% O-2). We find elevated basal T beta 4 protein expression in ECFC derived from prematurely born infants versus full term infants. T beta 4 is a potent growth hormone that additionally acts as an actin sequestration protein and regulates the stability of HIF-1 alpha. This basal level increase of T beta 4 is associated with lower HIF1 alpha nuclear localization in preterm versus term ECFC upon exposure to hyperoxia. We find altered expression in the pro-angiogenic genes vegf and eNOS, two genes that HIF-1 alpha acts as a transcription factor for. This provides a potential link between a developmentally regulated protein and previously observed impaired function of preterm ECFC in response to hyperoxia.

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Foroni, Laura <1978&gt. "Resident angiogenic mesenchymal stem cells from multiorgan donor thoracic aortas". Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2008. http://amsdottorato.unibo.it/976/.

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Stem cells are one of the most fascinating areas of biology today, and since the discover of an adult population, i.e., adult Stem Cells (aSCs), they have generated much interest especially for their application potential as a source for cell based regenerative medicine and tissue engineering. aSCs have been found in different tissues including bone marrow, skin, intestine, central nervous system, where they reside in a special microenviroment termed “niche” which regulate the homeostasis and repair of adult tissues. The arterial wall of the blood vessels is much more plastic than ever before believed. Several animal studies have demonstrated the presence of cells with stem cell characteristics within the adult vessels. Recently, it has been also hypothesized the presence of a “vasculogenic zone” in human adult arteries in which a complete hierarchy of resident stem cells and progenitors could be niched during lifetime. Accordingly, it can be speculated that in that location resident mesenchymal stem cells (MSCs) with the ability to differentiate in smooth muscle cells, surrounding pericytes and fibroblasts are present. The present research was aimed at identifying in situ and isolating MSCs from thoracic aortas of young and healthy heart-beating multiorgan donors. Immunohistochemistry performed on fresh and frozen human thoracic aortas demonstrated the presence of the vasculogenic zone between the media and the adventitial layers in which a well preserved plexus of CD34 positive cells was found. These cells expressed intensely HLA-I antigens both before and after cryopreservation and after 4 days of organ cultures remained viable. Following these preliminary results, we succeeded to isolate mesenchymal cells from multi-organ thoracic aortas using a mechanical and enzymatic combined procedure. Cells had phenotypic characteristics of MSC i.e., CD44+, CD90+, CD105+, CD166+, CD34low, CD45- and revealed a transcript expression of stem cell markers, e.g., OCT4, c-kit, BCRP-1, IL6 and BMI-1. As previously documented using bone marrow derived MSCs, resident vascular wall MSCs were able to differentiate in vitro into endothelial cells in the presence of low-serum supplemented with VEGF-A (50 ng/ml) for 7 days. Under the condition described above, cultured cells showed an increased expression of KDR and eNOS, down-regulation of the CD133 transcript, vWF expression as documented by flow cytometry, immunofluorescence, qPCR and TEM. Moreover, matrigel assay revealed that VEGF induced cells were able to form capillary-like structures within 6 hours of seeding. In summary, these findings indicate that thoracic aortas from heart-beating, multi-organ donors are highly suitable for obtaining MSCs with the ability to differentiate in vitro into endothelial cells. Even though their differentiating potential remains to be fully established, it is believed that their angiogenic ability could be a useful property for allogenic use. These cells can be expanded rapidly, providing numbers which are adequate for therapeutic neovascularization; furthermore they can be cryostored in appropriate cell banking facilities for later use.

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Milewski, Michael Edward. "The Angiogenic effect of Erythropoietin on Stem Cells In-Vitro". Master's thesis, Temple University Libraries, 2011. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/127595.

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Biology
M.S.
Angiogenesis is a normal and vital process that occurs during growth and development. Repair of bony defects, whether in the craniofacial complex or the alveolus, require an alloplastic or xenoplastic bone graft with angiogenic potential. This angiogenic potential is derived from existing blood vessels adjacent to the graft site. Improving the endogenous angiogenic potential with a molecule would drastically improve the survival rate of the bone graft material. This study was conducted to test the hypothesis that specific stem cell lines treated with erythropoietin, a positive promoter of angiogenesis, may increase the erythropoietin receptor expression in-vitro. In addition, this study also evaluated the vascular branching in vitro of human umbilical vein-derived endothelial cells treated with erythropoietin in the matrigel assay. Human umbilical vein-derived endothelial cells were treated for seven days with four concentrations of erythropoietin and cellular branching was evaluated in the matrigel assay. human bone marrow-derived mesenchymal stem cells and multi-potent cord blood derived unrestricted stromal stem cells were treated for seven days with erythropoietin and erythropoietin receptor expression was evaluated via reverse transcriptase real time polymerase chain reaction and real time polymerase chain reaction assays. The results of this study indicate that: erythropoietin had no effect on human umbilical vein-derived endothelial cells in the matrigel assay from a qualitative perspective, after treating multi-potent cord blood derived unrestricted stromal stem cells cells for 7 days with erythropoietin, there was no statistically significant difference between treatment groups when compared to control, and after treating human bone marrow-derived mesenchymal stem cells cells for 7 days with erythropoietin, the 20 U/ml treatment group showed a statistically significant reduction of the erythropoietin receptor as compared to the control group.
Temple University--Theses

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Latham, Nicholas. "Second Generation Cardiac Cell Therapy: Combining Cardiac Stem Cells and Circulating Angiogenic Cells for the Treatment of Ischemic Heart Disease". Thèse, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/24293.

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Blood-derived circulatory angiogenic cells (CACs) and resident cardiac stem cells (CSCs) have both been shown to improve cardiac function after myocardial infarction (MI) but the superiority of either cell type has long been an area of speculation with no definitive head-to-head trial. In this study, we compared the paracrine profile of human CACs and CSCs, alone or in combination. We characterized the therapeutic ability of these cells to salvage myocardial function in an immunodeficient mouse model of MI by transplanting these cells as both single and dual cell therapies seven days after experimental anterior wall MI. CACs and CSCs demonstrated unique paracrine repertoires with equivalent effects on angiogenesis, stem cell migration and myocardial repair. Combination therapy with both cell types synergistically improves post infarct myocardial function greater than either therapy alone. This synergy is likely mediated by the complementary paracrine signatures that promote revascularization and the growth of new myocardium.

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Giordano, Céline. "Pre-Clinical Evaluation of Biopolymer Delivered Circulating Angiogenic Cells in Hibernating Myocardium". Thèse, Université d'Ottawa / University of Ottawa, 2011. http://hdl.handle.net/10393/20619.

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Vasculogenic cell-based therapy combined with tissue engineering is a promising revascularization strategy for patients with hibernating myocardium, a common clinical condition. We used a clinically relevant swine model of hibernating myocardium to examine the benefits of biopolymer-supported delivery of circulating angiogenic cells (CACs) in this context. Twenty-five swine underwent placement of an ameroid constrictor on the left circumflex artery (LCx). After 2 weeks, positron emission tomography measures of myocardial blood flow (MBF) and myocardial flow reserve (MFR) were reduced in the affected region (both p<0.001). Hibernation (mismatch) was specific to the LCx territory. Swine were randomized to receive intramyocardial injections of PBS control (n=10), CACs (n=8), or CACs + a collagen-based matrix (n=7). At follow-up, stress MBF and MFR were increased only in the cells+matrix group (p<0.01), and mismatch was lower in the cells+matrix treated animals (p=0.02) compared to controls. Similar results were found using microsphere-measured MBF. Wall motion abnormalities and ejection fraction improved only in the cells+matrix group. This preclinical swine model demonstrated ischemia and hibernation, which was improved by the combined delivery of CACs and a collagen-based matrix. To our knowledge, this is the first demonstration of the mechanisms and effects of combining progenitor cells and biopolymers in the setting of myocardial hibernation, a common clinical condition in patients with advanced coronary artery disease.

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Ward, K. L. "Analysing the angiogenic potential of mesothelial cells in vitro and in vivo". Thesis, University of Liverpool, 2017. http://livrepository.liverpool.ac.uk/3008101/.

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Webster, Katie Elizabeth. "Angiogenesis in endometriosis : the role of circulating angiogenic cells and the endometrium". Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:33c8921c-8320-4559-8298-52d85c8a2987.

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Endometriosis is a common cause of subfertility and pelvic pain, affecting up to 10% of women of reproductive age. It is characterised by the presence of endometrial-like tissue outside the uterus. The development of the disease is still poorly understood and, currently, the diagnosis relies on visualisation of typical lesions during surgery. There is great interest in identifying biomarkers to assist in diagnosis and disease management. Blood vessel development is known to be a crucial feature of endometriosis, but the mechanisms involved in angiogenesis are not well described for this disease. Most vessel development relies on the proliferation and migration of pre-existing endothelial cells. However, there may also be roles for cells derived from peripheral blood (circulating angiogenic cells) and surrounding stromal cells. In this thesis, the contribution of these different cell types to vessel development in endometriosis is assessed. In chapter 2, a robust protocol was optimised to identify circulating angiogenic cells (CACs) with flow cytometry. The reliability of the protocol was verified, and the level of these cells was found not to fluctuate with the menstrual cycle in healthy women (P=0.279, F=1.359, 3 d.f.). In chapter 3, levels of CACs in women with and without endometriosis were found to be equivalent (0.0835% ± 0.0422 compared to 0.0724% ± 0.0414), demonstrating that they have no use as a disease biomarker. In chapter 4, isolation and culture of endothelial cells from the endometrium was attempted. However, a pure culture of endometrial endothelial cells could not be obtained, which may be due to contamination by other cell types or cellular transdifferentiation. Finally, in chapter 5, the contribution of endometrial stromal cells to vessel development was considered. Stromal cells were found not to differentiate towards an endothelial cell phenotype, but were able to participate in tube formation assays. However, the presence of endometriosis did not influence this behaviour.

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Zhuge, Xin. "CXCL16 is a novel angiogenic factor for human umbilical vein endothelial cells". Kyoto University, 2005. http://hdl.handle.net/2433/144481.

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Russell, Hugh. "Early angiogenic change in dental pulp stromal cells cultured on biomimetic matrices". Thesis, University of Leeds, 2016. http://etheses.whiterose.ac.uk/13395/.

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Revascularisation of the devitalised root canal is the Holy Grail of Endodontics and is being hotly pursued by many teams of clinicians but has yet to be achieved. The overall aim of this work was to attempt to induce early angiogenesis in human dental pulp stromal cells (DPSCS) in vitro and in vivo using a biomimetic approach based on combining scaffolds comprised of ECM components with DPSCs as a first step towards a tissue engineering strategy for dental pulp regeneration. After isolating DPSCs using collagenase digest, they were cultured on 1% hyaluronic acid (HyA) or Types I and III collagen matrices used either singly or in combination to determine the ability of these scaffolds to support/induce early angiogenic change in DPSCs both in vitro and in vivo. Angiogenic change was determined using a combined approach of DNA quantification, histology, immunohistochemistry to detect the angiogenic markers CD31 and CD34 and quantitative RT-PCR. DPSCs were shown to attach and proliferate on Type I and III collagen membranes in vitro but early angiogenic change in vitro was evidenced only when 1% HyA gel was used, including in the absence of the morphogen rhVEGF165 as shown immunohistochemically. PCR at two and five days post-seeding showed an up-regulation of CD31 and CD34 genes dependant on culture conditions, with CD31 being upregulated early and CD34 later in the culture period. A modified tooth slice model containing a combination of HyA/collagen scaffold/DPSC constructs within its lumen also showed positive early angiogenic change in vitro. SEM examination further confirmed that DPSCs could attach, colonise and proliferate to/on the combined scaffold. The same combined scaffold-tooth slice model ± DPSCs used in vivo in nude mice showed cellular ingress into the lumen with a soft tissue closely resembling dental pulp-like tissues in its appearance with new tubule-like material grown on from the dentinal tubules of the tooth slice. There was a defined demarcation line between this latter material and the dentinal tubules of the tooth slice and the new material closely resembled predentine or dentine-like matrix in appearance and stained strongly for CD31 and CD34 markers. It also had a layer of cells adjacent to and in intimate contact with its deposition front, whose cell processes transited the new tubule-like material and continued into the dentine tubules of the tooth slice for some distance. Interestingly, this neo-tissue was independent of the addition of DPSCs to the construct. The results suggest that biomimetic scaffolds based upon components of the pulp extracellular matrix may provide a useful platform for future engineering of a vascularised replacement dental pulp.

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Ostojic, Aleksandra. "Use of a Collagen I Matrix to Enhance the Potential of Circulating Angiogenic Cells (CACs) for Therapy". Thesis, Université d'Ottawa / University of Ottawa, 2015. http://hdl.handle.net/10393/31931.

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Acute myocardial infarction (MI) is the end result of many cardiovascular diseases and is one of the leading causes of death in the western world. Cell therapy, using circulating angiogenic cells (CACs) or CD34+ cells from peripheral blood, is one approach under investigation for restoring blood flow and function to the ischemic heart. However, the numbers of CACs and CD34+ circulating cells are inversely proportional to the severity of cardiovascular disease and age; therefore, there is a need to increase their numbers and/or function for therapy. One possibility is to enhance the therapeutic potential of the cells with the use of a biomaterial. In this study, we used a collagen matrix to culture human CD34+ circulating cells, and evaluated the effect of the matrix on CD34+ cell properties and function. The matrix was able to successfully increase proliferation, migration, CD34+ phenotype and branching in an angiogenesis assay. These functional benefits may be associated with the sonic hedgehog (Shh) pathway. The collagen matrix was previously shown to enhance the function of healthy CACs, but its ability to do the same for CACs from coronary artery disease patients is unknown. In this study, the matrix was shown to enhance the viability, proliferation and angiogenic potential of patient CACs. Furthermore, gene expression for integrins and Shh pathway components in the sub-population of CD34+ cells was similar between patient and healthy donors when isolated from CACs. This work provides insight into the mechanisms for the observed matrix-enhanced function of therapeutic CACs and CD34+ cells from both healthy and CAD patient donors.

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Ye, Qinmao. "Exosomes Released from Multiple Myeloma Cells Influence the Angiogenic Function of Endothelial Cells by Regulating MicroRNA-29b". Wright State University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=wright1532474227694747.

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Angara, Kartik Prasad. "CXCR2 Expressing Tumor Cells Drive Vascular Mimicry in Anti-angiogenic Therapy Resistant Glioblastoma". Thesis, Augusta University, 2018. http://pqdtopen.proquest.com/#viewpdf?dispub=10839522.

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Glioblastoma (GBM) is a hypervascular and hypoxic neoplasia of the central nervous system with an extremely high rate of mortality. Owing to its hypervascularity, anti-angiogenic therapies (AAT) have been used as an adjuvant to the traditional surgical resection, chemotherapy, and radiation to normalize blood vessels, control abnormal vasculatures and prevent recurrence. The benefits of AAT have been transient and the tumors were shown to relapse faster and demonstrated particularly high rates of AAT-induced therapy resistance due to activation of alternative neovascularization mechanisms. Vascular Mimicry (VM) is the uncanny ability of tumor cells to acquire endothelial-like properties, lay down vascular patterned networks reminiscent of host endothelial blood vessels and served as an irrigation system for the tumors to meet with the increasing metabolic and nutrient demands in the event of the ensuing hypoxia resulting from AAT. In our studies, we have demonstrated that AAT accelerates VM. We observed that Vatalanib (a VEGFR2 tyrosine kinase inhibitor) induced VM vessels are positive for periodic acid-Schiff (PAS) matrix but devoid of any endothelium on the inner side and lined by tumor cells on the outer side. Interestingly, 20-HETE synthesis inhibitor HET0016 significantly decreased GBM tumors through decreasing VM structures both at the core and at the periphery of the tumors. During our extensive studies to understand the tumor-inherent mechanisms of AAT-induced resistance, we identified a crucial chemokine, CXCL8 or IL-8, to be highly upregulated in the GBM tumors treated with AAT. IL-8 has been well established as a highly prevalent cytokine in GBM with potent pro-migratory and pro-angiogenic functions. AAT-treated groups had significantly higher populations of CXCR2+ glioma stem cells and endothelial-like subpopulations and these populations were decreased following treatment with HET0016 and SB225002 (a CXCR2 antagonist). CXCR2+ GBM tumor cells were shown to form VM-like vascular channels carrying functional RBCs. Knocking down CXCR2 led to smaller tumor size in the animals and improperly developed vascular structures without CXCR2+ GBM cells lining them. This confirms our hypothesis that CXCR2+ GBM cells initiate VM and contribute to AAT resistance in GBM. Our present study suggests that HET0016 and SB225002 have potential to target therapeutic resistance and can be combined with other antitumor agents in preclinical and clinical trials.

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Farjood, Farhad. "Effect of Physical Stimuli on Angiogenic Factor Expression in Retinal Pigment Epithelial Cells". DigitalCommons@USU, 2019. https://digitalcommons.usu.edu/etd/7457.

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Age-related macular degeneration (AMD) is a major cause of blindness in adults. Abnormal growth of blood vessels in the eye during the course of AMD causes damage to the retina, resulting in irreversible blindness. The goal of this research was to determine whether physical pressure on retinal cells can contribute to the increased blood vessel formation. To replicate the tears in the cell layers, a micropatterning method was used as a means of detaching cells from each other. Two new devices were also developed to mimic slow and fast increases in mechanical pressure on cell layers of the eye. After detaching cells from each other and adding mechanical stress to cells, the levels of angiogenic proteins secreted by retinal cells were measured. The results showed that both cell-cell detachment and mechanical stress can increase the secretion of angiogenic proteins. After adding mechanical stress, we also added the secreted proteins to blood vessel cells and observed an increase in blood vessel formation, indicating that mechanical stress can independently induce angiogenesis. These results suggest that physical stimuli in the eye can contribute to the aberrant blood vessel formation in AMD.

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Lewis, Deana L. "Angiogenic Characteristics of Tumor-Associated Dendritic Cells in Ovarian and Breast Cancer Models". Ohio University Art and Sciences Honors Theses / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ouashonors1462296303.

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Ramakrishnan, Devi Prasadh. "Mechanisms of Anti-Angiogenic Signaling by CD36". Case Western Reserve University School of Graduate Studies / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1417004434.

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Pasupuleti, Vinay. "A novel peptide derived from the functional domain of AGGF1 has anti-angiogenic activity". Kent State University / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=kent1310957711.

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Andriu, Alexandra. "Evaluating the utility of αvβ3 integrin antagonists to detect and treat angiogenic tumour cells". Thesis, University of Aberdeen, 2018. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=240026.

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Tumour angiogenesis, the formation of new blood vessels within a tumour, is a hallmark of cancers, that allows them to grow beyond a critical size and to metastasize to other organs. As the key driver of tumour angiogenesis, αvβ3 integrin is both an established therapeutic target for anti-angiogenic drugs and a biomarker for imaging agents. Accurate detection of αvβ3 integrin in angiogenic tumours impacts patient prognosis and could report on therapy response. Over the last twenty years, novel αvβ3 integrin-targeted radiotracers have been developed for PET imaging of tumour angiogenesis. While most radiotracers have shown their utility as diagnostic tools, only a few focussed on evaluating response to treatment, partly due to complex biology of the integrin receptors. The aim of this project was the in-vitro biological testing of a novel αvβ3-targeted radiotracer, [3H]ZMPZAT71, and the corresponding unlabelled compound for targeted delivery of a cytotoxic drug, paclitaxel (PTX). Firstly, this piece of work involved validation of this radiotracer to assess expression of αvβ3 integrin. Secondly, [3H]ZMPZAT71 was investigated as a biomarker for assessing response to pharmacological inhibitors of cell signalling pathways. Thirdly, the targeting moiety (ZMPZAT71) conjugated with paclitaxel was studied for integrinmediated drug delivery. The results presented herein demonstrate that radiotracer binding to αvβ3 integrin is dependent not only on the expression levels, but also on the activation status of αvβ3 integrin. Furthermore, this piece of information was used to explain radiotracer binding in response to various pharmacological inhibitors of key cell signalling pathways. Additionally, the integrin-targeted chemotherapeutic exhibited selective cytotoxic effect, explained by enhanced apoptosis of cancer cells compared to PTX alone, together with anti-migratory and anti-invasive effects from the targeting moiety. This study provides valuable information about the molecular mechanisms regulated by αvβ3 integrin, supporting the development of integrin-targeted therapeutics and imaging.

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Pranjol, Md Zahidul Islam. "Regulation of angiogenic processes in omental endothelial cells during metastasis of epithelial ovarian cancer". Thesis, University of Exeter, 2017. http://hdl.handle.net/10871/29914.

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Epithelial ovarian cancer frequently metastasizes to the omentum, a process that requires pro-angiogenic activation of local microvascular endothelial cells (ECs) by tumour-secreted factors. We have previously shown that ovarian cancer cells secrete factors, other than vascular endothelial growth factor (VEGF), with possible roles in metastatic angiogenesis including the lysosomal proteases cathepsin L (CathL) and cathepsin D (CathD), and insulin-like growth factor binding protein 7 (IGFBP7). However, the mechanisms by which these factors may contribute to omental endothelial angiogenic changes are unknown. Therefore the aims of this thesis were a) to examine disease relevant human omental microvascular endothelial cell (HOMEC) proliferation, migration and angiogenesis tube-formation induced by CathL, CathD and IGFBP7; b) to investigate whether CathL and CathD act via a proteolytic or non-proteolytic mechanism; c) to identify activated downstream intracellular signalling cascades in HOMECs and their activation in proliferation and migration; and finally d) to identify activated cell surface receptors by these factors. CathL, CathD and IGFBP7 significantly induced proliferation and migration in HOMECs, with CathL and CathD acting in a non-proteolytic manner. Proteome-profiler and ELISA data identified increased phosphorylation of the ERK1/2 and AKT (protein kinase B) pathways in HOMECs in response to these factors. CathL induced HOMEC proliferation and migration via the ERK1/2 pathway, whereas, although CathD-induced proliferation was mediated by activation of ERK1/2, its migratory effect was dependent on both ERK1/2 and AKT pathways. Interestingly, CathL induced secretion of galectin-1 (Gal1) from HOMECs which in turn significantly induced HOMEC proliferation via ERK1/2. However, none of the ERK1/2 or AKT pathways was observed to be active in Gal1-induced HOMEC migration. Interestingly, Gal1-induced proliferation and migration were significantly inhibited by L-glucose, suggesting a role for a receptor with extracellular sugar moieties. IGFBP7-induced migration was shown to be mediated via activation of the ERK1/2 pathway only. CathL, Gal1 and IGFBP7 significantly induced angiogenesis tube-formation in HOMECs which was not observed in CathD-treated cells. Receptor tyrosine kinase array revealed activation of Tie-1 and VEGF receptor type 2 (VEGFR2) in CathL and IGFBP7-treated HOMECs respectively. In conclusion, all CathL, CathD, Gal1 and IGFBP7 have the potential to act as proangiogenic factors in the metastasis of ovarian cancer to the omentum. These in vitro data suggest all four factors activate intracellular pathways which are involved in well-known angiogenesis models.

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Ross, Mark D. "The influence of age, cardiorespiratory fitness, exercise and sedentary behaviours on circulating angiogenic cells and cell surface receptor expression". Thesis, Edinburgh Napier University, 2016. http://researchrepository.napier.ac.uk/Output/10295.

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Cardiovascular disease (CVD) is the biggest killer of people in western civilisation. Age is a significant risk factor for the development for CVD, and treatments and therapies to address this increased risk are crucial to quality of life and longevity. Exercise is one such intervention which has been shown to reduce CVD risk. Age is also associated with endothelial dysfunction, reduced angiogenic capabilities, and reduced ability to repair the vessel wall. Circulating angiogenic cells (CACs) are a subset of circulating cells which assist in the repair and growth of the vasculature and in the maintenance of endothelial function. Reductions in these cells are observed in those with vascular disease compared to age-matched healthy controls. Exercise may reduce CVD risk by improvements in number and/or function of these CACs. Data was collected from human volunteers of various ages, cardiorespiratory fitness (CRF) levels and latent viral infection history status to investigate the effects of chronological age, CRF, viral serology and other lifestyle factors, such as sedentary behaviours and exercise on CACs. The levels of CACs in these volunteers were measured using four colour flow cytometry using various monoclonal antibodies specific to cell surface markers that are used to identify specific subsets of these CACs. In addition, the response to acute exercise of a specific subset of these CACs, termed ‘angiogenic T-cells' (TANG) were investigated, in a group of well-trained males aged 20-40 years, using a strenuous submaximal exercise bout. Advancing age was associated with a decline in various subsets of CACs, including bone marrow-derived CD34+ progenitors, putative endothelial progenitor cells (EPCs) and also TANG cells. Individuals with a higher CRF were more likely to have higher circulating numbers of TANG cells, particularly in the CD4+ subset. CRF did not appear to modulate CD34+ progenitors or EPC subsets. Increasing sitting time was associated with reduction in TANG cells, but after correcting for the effects of fitness, sitting time no longer negatively affected the circulating number of these cells. Acute exercise was a powerful stimulus for increasing the number of TANG cells (140% increase), potentially through an SDF-1:CXCR4-dependent mechanism, but more studies are required to investigate this. Latent CMV infection was associated with higher number of TANG cells (CD8+), but only in 18-40 year old individuals, and not in an older age group (41-65 year old). The significance of this has yet to be understood. In conclusion, advancing age may contribute to increased CVD risk partly due to the observed reductions in angiogenic cells circulating in the peripheral compartment. Maintaining a high CRF may attenuate this CVD reduction by modulating TANG cell number, but potentially not CD34+ progenitor or EPC subsets. Acute exercise may offer a short window for vascular adaptation through the mobilisation of TANG cells into the circulation.

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Hein, Melanie [Verfasser] y Manfred [Gutachter] Gessler. "Functional analysis of angiogenic factors in tumor cells and endothelia / Melanie Hein. Gutachter: Manfred Gessler". Würzburg : Universität Würzburg, 2014. http://d-nb.info/1112040110/34.

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Yahyouche, Asma. "Evaluation of channels for angiogenic cells ingrowth in collagen scaffolds in vitro and in vivo". Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:55835c59-0ef7-40ec-b5dd-f6ae901f1151.

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Pre-cellularised scaffolds are limited in volume due to the constraints of the time delay required for angiogenic cells ingrowth forming a vascular network and allowing for delivery of nutrients and waste exchange. Channels have the potential to improve the time taken for cellular penetration. The effectiveness of channels in improving angiogenic cells penetration was assessed in vitro and in vivo in porous 3-D collagen scaffolds. Initial studies conducted in vitro demonstrated that the scaffolds supported angiogenic cells ingrowth in culture and the channels improved the depth of penetration of cells into the scaffold. The cells reside mainly around the channels and migrate along the channels. In vivo, channels increased cell migration into the scaffolds and in particular angiogenic cells resulting in a clear branched vascular network of micro vessels in the channelled samples which was not apparent in the non-channelled samples. This correlated well with macrophage invasion into scaffolds since angiogenesis in vivo is usually accompanied by infiltration of macrophages which participate in organization of angiogenesis, and in regulation of tissue regeneration. Thus, macrophage-mediated biodegradation of collagen scaffolds in vitro was also assessed. Furthermore, pre-seeding channelled collagen scaffolds with endothelial cells implantation has potential of speeding up vascularisation of scaffolds compared to human bone marrow stromal cells.

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McGuire, David Robert. "Silencing Endothelial EphA4 Alters Transcriptional Regulation of Angiogenic Factors to Promote Vessel Recovery Following TBI". Thesis, Virginia Tech, 2020. http://hdl.handle.net/10919/99318.

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Traumatic brain injury (TBI) can cause a number of deleterious effects to the neurovascular system, including reduced cerebral blood flow (CBF), vascular regression, and ischemia, resulting in cognitive decline. Research into therapeutic targets to restore neurovascular function following injury has identified endothelial EphA4 receptor tyrosine kinase as a major regulator of vascular regrowth. The research outlined herein utilizes an endothelial-specific EphA4 knockout mouse model (KO-EphA4flf/Tie2-Cre) to determine the extent to which this receptor may influence vascular regrowth following TBI. Analysis of the colocalization and proximity of endothelial and mural cell markers (i.e. PECAM-1 and PDGFRβ, respectively) in immunohistochemically-stained brain sections demonstrates that EphA4 silencing does not seem to affect the physical association between, nor total amounts of, endothelial cells and pericytes, between genotypes by 4 days post-injury (dpi). Nevertheless, these measures demonstrate that these cell types may preferentially proliferate and/or expand into peri-lesion tissue in both KO-EphA4flf/Tie2-Cre) and WT-EphA4fl/fl mice. These data further suggest that both genotypes experience homogeneity of PECAM-1 and PDGFRβ expression between regions of the injury cavity. Gene expression analysis using mRNA samples from both genotypes reveals that KO-EphA4flf/Tie2-Cre CCI-injured mice experience increased expression of Vegfa, Flt1, and Fn (Fibronectin) compared to sham-injured condition knockouts. These results demonstrate changes in expression of angiogenic factors in the absence of early differences in patterns of vessel formation, which may underlie improved vascular regrowth, as well as outline a potential mechanism wherein the interplay between these factors and EphA4 silencing may lead to improved cognitive outcomes following TBI.
Master of Science
Every day in the United States, an average of 155 people die due to the consequences of traumatic brain injury (TBI), with many survivors suffering life-long debilitating effects, including deficits in behavior, mobility, and cognitive ability. Because of this, there is a need for researchers to identify therapeutic strategies to stimulate recovery and improve patient outcomes. Recent advancements in the field of vascular biology have identified the regrowth of the blood vessels in the brain following TBI-induced damage as an important step in the recovery process, since the resulting increases in blood flow to damaged tissue will provide oxygen and nutrients necessary to fuel recovery. The work presented in this Masters thesis follows in this vein by examining a protein receptor known as EphA4, which is found on cells within blood vessels and has been implicated in reducing the rate of vessel growth under injury conditions. By blocking the activity of EphA4, we hoped to find increased vascular regrowth following brain injury in mice. During the experiments outlined herein, it was found that there were no statistically significant differences in vessel-associated cell densities between mice with or without EphA4 activity 4 days after injury, but there were differences in the levels of proteins and/or signals associated with vessel growth. Based on these results, we conclude that removing EphA4 activity increases expression of these pro-vessel growth proteins in mouse brains following injury at these early time points, potentially leading to increased vessel growth and improved recovery over subsequent weeks following injury.

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23

McEwan, Kimberly A. "Synthesis and Characterization of Tissue-engineered Collagen Hydrogels for the Delivery of Therapeutic Cells". Thèse, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/23935.

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The expanding field of tissue engineering provides a new approach to regenerative medicine for common ailments such as cardiovascular disease and type-I diabetes. Biomaterials can be administered as a delivery vehicle to introduce therapeutic cells to sites of damaged or diseased tissue. A specific class of biomaterials, termed hydrogels, is suitable for this application as they can provide a biocompatible, biodegradable scaffold that mimics the physical properties of the native soft tissue. Injectable hydrogels are increasingly being developed for biomedical applications due to their ability to be delivered in a minimally invasive manner. One potential use for such materials is in the delivery of therapeutics such as cells or growth factor-releasing particles. In this study, the first aim was to determine the interactive effects between collagen-based hydrogels and additives (cells and microspheres) for cardiac regeneration. The results demonstrated that the addition of either cells or microspheres to a collagen-based hydrogel decreased its gelation time and increased its viscosity. Increased cross-linker concentrations resulted in lower cell viability. However, this cell loss could be minimized by delivering cells with the cross-linker neutralizing agent, glycine. As a potential application of these materials, the second aim of this study was to develop a hydrogel for use as an ectopic islet transplant site. Specifically, collagen-chitosan hydrogels were synthesized and characterized, with and without laminin, and tested for their ability to support angiogenic and islet cell survival and function. Matrices synthesized with lower chitosan content (20:1 collagen:chitosan) displayed greater cell compatibility for both angiogenic cells and for islets and weaker mechanical properties, while matrices with higher chitosan content (10:1 collagen:chitosan) had the opposite effect. Laminin did not affect the physical properties of the matrices, but did improve angiogenic cell and islet survival and function. Overall the proposed collagen-based hydrogels can be tailored to meet the physical property requirements for cardiac and islet tissue engineering applications and demonstrated promising cell support capabilities.

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24

Zhang, Hua-Tang. "Transfection of angiogenic factors into human MCF-7 breast carcinoma cells : effects on growth in vivo". Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.308606.

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25

Sofrenovic, Tanja. "Evaluation of an Enhanced (Sialyl Lewis-X) Collagen Matrix for Neovascularization and Myogenesis in a Mouse Model of Myocardial Infarction". Thesis, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/22747.

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In cardiovascular disease the repair response is insufficient to restore blood flow, leading to the death of muscle and loss of tissue function. Therefore, strategies to augment the endogenous cell response and its effects may help improve tissue recovery and function. In this study we explored the use of tissue-engineered collagen matrices for augmenting endogenous regenerative processes after myocardial infarction. Treatment with the sLeX-collagen matrix reduced inflammation and apoptosis and had a positive regenerative effect on the infarcted mouse heart, through improved vascular density and possibly enhanced cardiomyogenesis. Additionally, we investigated the effects of cryopreservation on generating circulating angiogenic cells (CACs) from peripheral blood mononuclear cells (PBMCs), as a potential source of stem cells that could be used in combination with our collagen scaffold. Our findings show that despite PBMCs experiencing phenotypic changes after cryopreservation, they may still be used to generate the same therapeutic CACs as freshly procured PBMCs.

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26

Balaji, Swathi. "In situ tissue engineering using angiogenic peptide nanofibers to enhance diabetic wound healing". University of Cincinnati / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1291151135.

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27

Andrikopoulos, Petros. "The effect of ionic fluxes on cell signalling and the angiogenic properties of human umbilical vein vascular endothlial cells ( HUVECs) in vitro". Thesis, Imperial College London, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.520939.

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28

Möller, Björn. "Human endometrial angiogenesis : an immunohistochemical study of the endometrial expression of angiogenic growth factors and their corresponding receptors /". Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3900.

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29

Deshane, Jessy S. "Regulation of HO-1 and its role in angiogenesis". Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2007. https://www.mhsl.uab.edu/dt/2009r/deshane.pdf.

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30

Lam, In Kei. "Anti-angiogenic activities of flavonoids from Pericarpium Citri Reticulatae on human umbilical vein endothelial cells (HUVECs) and zebrafish". Thesis, University of Macau, 2010. http://umaclib3.umac.mo/record=b2447360.

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31

Gourlaouen, Morgane. "Receptor internalisation in endothelial cells is required for signalling and angiogenesis in response to pro-angiogenic growth factors". Thesis, Institute of Cancer Research (University Of London), 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.545930.

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32

Chambers, Sarah Elizabeth Jane. "Analysis of the vasoreparative and anti-inflammatory potential of circulating angiogenic cells (CACS) for the treatment of diabetic retinopathy". Thesis, Queen's University Belfast, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.695297.

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Interest in regenerative medicine is increasing, in particular, the use of cell-based therapies for treatment of ischaemic diseases has renewed hope of finding a cure, beyond the treatment of symptoms. CAC-based cytotherapy significantly enhances vascular repair in the murine ischaemic retina and is mediated by paracrine release of angiogenic factors. This pro-angiogenic potential of CACs could be harnessed as a novel cellular therapy for the treatment of DR. However, CACs are dysfunctional in diabetes and raises concerns that exposure to the diabetic milieu alters CACs to a phenotype that could exacerbate pathology, rather than repair it. The aim of this thesis is to define the precise phenotype of CACs and their angiogenic properties in the context of hyperglycaemia, and to further the development of CACs as a potential clinical application for therapeutic angiogenesis, that is safe and feasible. CACs were isolated from human peripheral blood mononuclear cells that were cultured on fibronectin-coated flasks with endothelial media for 7 days. CACs are not definite M2 macrophages, but represent a distinct subtype of macrophage or macrophage-like cell that share M2 characteristics - anti-inflammatory, pro-angiogenic. CACs conditioned media (CM) can promote tube formation in endothelial cells; however, CACs CM pro-angiogenic potential is reduced when cells are exposed to high D-glucose treatment in vitro. This is due to a change in phenotype towards a pro-inflammatory profile by two potential mechanisms: up-regulation of IL 1 J3, or imbalance of MMP-91TIMP-1 ratio. CACs from type 1 diabetic patients were assessed in comparison to non-diabetic CACs and based on their M1/M2 profile, significant differences were found such as a decrease in CD163 and CD209 expression. This forms foundations for the study of the phenotypic differences in CACs when they are isolated from or delivered to the diabetic milieu. CACs were also isolated from mice bone marrow and characterised. This is an important step towards delivery of these cells in vivo. This project identified that a switch in phenotype is an important consideration when delivering CACs as a cell therapy into a diabetic environment. It highlights that more research is required to understand how CACs behave in vivo, and the plasticity of their M2-like phenotype, before these cells can be used successfully as a cellular therapy.

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33

Amirrasouli, Muhammad Mehdi. "Characterisation of cardiosphere derived cells : investigating hypoxic pre-conditioning on pro-angiogenic properties and tracking the cardiac fibroblast component". Thesis, University of Newcastle upon Tyne, 2014. http://hdl.handle.net/10443/2570.

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Coronary heart disease is still the leading cause of death in the UK, despite significant advances in clinical treatments. Stem cell transplantation has the potential to improve cardiac function and patient outcome, but optimal cell types, cell preparation methods and cell delivery routes are yet to be established. The heart contains a small population of progenitor cells that, in culture, contribute to spontaneously formed spheroids known as cardiospheres (Csphs). Following further culture, Csphs give rise to cardiosphere derived cells (CDCs). Both Csphs and CDCs show paracrine benefit including neovascularisation in myocardial ischaemia, leading to improvement in heart function. The aims of this project were to use mouse models to (i) investigate the effect of hypoxic preconditioning on the pro-angiogenic potential of CDCs and (ii) characterise the contribution of cardiac fibroblasts (CFs) to CDCs. I used Col1a2-CreERT;Rosa26-STOP-YFP mice to track YFP-expressing CFs in myocardial tissue and in CDC culture. Co-staining experiments showed only partial overlap of YFP with other CF markers (vimentin and Fsp1) in heart tissue, which may be due to the heterogeneity of CFs and/or incomplete activation of YFP in CFs. I showed that CF-derived cells exist in all stages of CDC culture, and a small subset of these cells also expressed the stem cell markers Sca-1 or cKit, suggesting CF derived cells may contribute to the progenitor cell population. My results showed that preconditioning CDCs with 3%O2 enhances cell outgrowth from heart explants and promotes expression of stem cell and pro-angiogenic markers. I then assessed the pro-angiogenic potential of CDCs in vivo using a sub-dermal matrigel plug assay and showed that CDCs alone have limited pro-angiogenic potential. However, 3%O2 preconditioning of CDCs significantly enhances this process. Further research will increase our understanding of CDC-mediated angiogenesis and improve clinical therapies for MI patients.

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34

Khalil, Alia. "Apolipoprotein L3 and Myeloperoxidase interfere with the angiogenic process via regulation of MAPK and Akt pathways". Doctoral thesis, Universite Libre de Bruxelles, 2017. https://dipot.ulb.ac.be/dspace/bitstream/2013/260994/4/thesis.pdf.

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Endothelial dysfunction is a broad term which implies alteration of the overall functions of endothelial cells, including impairment of the barrier functions, vasodilation, and disturbances in proliferative and angiogenic capacities, migratory as well as tube formation, and deterrence of leukocyte transmigration. Such a dysfunction is triggered by pro-inflammatory stimuli and has been associated to several pathological conditions including atherosclerosis. Myeloperoxidase is a heme peroxidase secreted by activated neutrophils at site of inflammation near blood vessels and plays an important role in the initiation of atherosclerotic plaque by interfering with endothelial function. ApoLs represent a family of newly discovered apolipoproteins with yet unrevealed function, but predicted to be involved in inflammatory processes and cell death mechanisms. We aimed to study the expression of ApoLs as well as Myeloperoxidase in endothelial cells and their possible contribution to endothelial dysfunction. We performed RNA sequencing on MPO-treated endothelial cells and found that most of the induced genes are related to angiogenesis and blood vessel morphogenesis mechanisms. MPO treatment resulted in intracellular MPO localization and mimicked the effects of VEGF on several signal transduction pathways, such as Akt, Erk and Fak involved in angiogenesis. Accordingly MPO, independently of its enzymatic activity, stimulated cellular proliferation, migration and tubules formation by endothelial cells. RNA interference also pointed at a role of endogenous MPO in tubulogenesis and endothelium wound repair in vitro.On the other hand, ApoL3 among other family members was shown to be a downstream responsive gene to MPO, VEGF and FGF treatment. ApoL3 invalidation reduces tubules formation in MPO and VEGF-induced angiogenesis and wound repair in vitro. Accordingly, pro-angiogenic signaling pathways (Erk1/2 and FAK but not Akt) and some pro-angiogenic genes were partially inhibited in ApoL3 Knock out cells. These findings uncover for the first time an important and unsuspected role for ApoL3 and MPO as drivers of angiogenesis.
Le dysfonctionnement endothélial est un terme qui désigne un dérèglement général de la fonction endothéliale, caractérisé par des perturbations de l’intégrité membranaire, de la croissance endothéliale, du rôle anti-inflammatoire ;anti-coagulant, ainsi que leur propriété angiogenique principalement la migration endothéliale et la formation des structures tubulaires. Cette condition patho-physiologique pourrait être déclenchée par des stimuli pro-inflammatoire et elle est souvent associée à l’athérosclérose. La myéloperoxydase est une enzyme secrétee par les neutrophiles et contribue à la formation de la plaque d’athérome. Une nouvelle famille de protéines, les apolipoprotéines L, susceptibles d'intervenir dans le processus inflammatoire est bien exprimée dans les cellules endothéliales. Néanmoins, aucune fonction ne lui a été attribuée jusqu’à présent dans ce type cellulaire.dans le cadre de ce travail, Nous nous sommes intéressés à étudier l’implication des ApoLs ainsi que la Myeloperoxydase dans la dysfonction endothéliale. L’analyse du transcriptome des cellules traitées avec la MPO a montré que lamajorité des génes induits contrôlent le processus angiogenique. La myeloperoxidase stimule la proliferation,migration et la tubulogenese des cellules endotheliales. Cet effet est médié par l’activation des cascades (ERK1/2, Akt et FAK) et des genes pro-angiogeniques. Tandis que la suppression de l’expression de la MPO endogène entraine l’inhibition de la capacité des cellules à migrer et de former des tubes.D’autre part, l’invalidation de l’ApoL3 inhibe la migration cellulaire et la tubulogenése dépendente de la MPO et le VEGF. Sur le plan mécanistique, ces altérations phénotypiques sont les conséquences d’une part, une baisse de phosphorylation des kinases Erk1/2 et FAk (mais pas Akt) et d’autre part de la réduction du taux d’expression des gènes pro-angiogeniques dans les cellules ApoL3 Knock out stimulées par la MPO et le VEGF. ce résultat nous permet de définir l’ApoL3 et la MPO en tant que nouvels acteurs dans le processus angiogenique.
Doctorat en Sciences
info:eu-repo/semantics/nonPublished

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35

Tang, Yubo. "Traditional Chinese Medicine extracts exert angiogenic and protective effects towards human endothelial progenitor cells: from cellular function to molecular pathway". Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-144400.

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Despite intense research efforts, the repair of large bone defects is still not satisfactory and remains a major challenge in Orthopaedic Surgery. In this context bone tissue engineering has emerged as a promising strategy. However, one of the fundamental principles underlying tissue engineering approaches is that newly formed tissue must maintain sufficient vascularization to support its growth. Thus an active blood vessel network is an essential pre-requisite for scaffold constructs to integrate within existing host tissue. Currently, great efforts are made to address this problem employing transplantation of vascular cells and loading of appropriate biological factors. Endothelial progenitor cells (EPCs) are a heterogeneous subpopulation of bone marrow mononuclear progenitor cells with potential for differentiation to the endothelial lineage and thus vasculogenic capacity. However, clinical studies reported that with the increase of age, increased susceptibility to apoptosis and accelerated senescence may contribute to the numerical and functional impairments observed in EPCs, which may lead to a reduced angiogenic capacity and an increased risk of vascular disease. Hence attention has increasingly been paid to enhance mobilization and differentiation of EPCs for therapeutic purposes. A large body of evidence indicates that in Traditional Chinese Medicine (TCM) a plethora of herbs and herbal extracts are effective in the treatment of vascular diseases such as chronic wounds, diabetic retinopathy and rheumatoid arthritis. Thus, it seems rational to explore these medicinal plants as potential sources of novel angiomodulatory factors. In this thesis we demonstrated that treatment with TCM herbal extracts promote cell growth, cell migration, cell-matrix and capillary-like tube formation of BM-EPCs. Among these TCM extracts, Salidroside (SAL) and Icariin (ICAR) incubation increased VEGF and nitric oxide secretion, which in turn mediated the enhancement of angiogenic differentiation of BM-EPCs. A mechanic evaluation provided evidence that SAL stimulates the phosphorylation of Akt, mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase (p70S6K), as well as phosphorylated ERK1/2, which is associated with the cell migration and tube formation. Furthermore, a pilot in vivo study showed that SAL has the potential to enhance bone formation in a murine femoral critical-size bone defects model. Another new finding of the present study is that hydrogen peroxide (H2O2)-induced cytotoxicity is counteracted by TCM extracts. We found that SAL, Salvianolic acid B (SalB) and ICAR significantly abrogated H2O2-induced cell apoptosis, reduced the intracellular level of reactive oxygen species (ROS) and nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) expression, and restored the mitochondrial membrane potential of BM-EPCs. Our data suggest that this protective effect of SalB is mediated by the activation of mTOR, p70S6K, 4EBP1, and by the suppression of MKK3/6-p38 MAPK-ATF2 and ERK1/2 signaling pathways after H2O2 stress. In addition, the investigation also demonstrates that ICAR owns the ability to inhibit apoptotic and autophagic programmed cell death via restoring the loss of mTOR and attenuation of ATF2 activity upon oxidative stress. Based on the outcomes of the present work, we propose SAL, SalB and ICAR as novel proanigiogenic and cytoprotective therapeutic agents with potential applications in the fields of systemic and site-specific tissue regeneration including ischaemic disease and extended musculoskeletal tissue defects.

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36

Kolar, Mallappa K. "The use of adipose derived stem cells in spinal cord and peripheral nerve repair". Licentiate thesis, Umeå universitet, Anatomi, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-89445.

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Clinically, injuries affecting the spinal cord or peripheral nerves can leave those affected with severe disability and, at present, there are limited options for treatment. Peripheral nerve injury with a significant gap between the proximal and distal stumps is currently treated with autologous nerve grafting but this is limited by availability of donor nerve and has associated morbidities. In contrast, injuries to the spinal cord lead to an inhibitory environment caused by the glial cells and thereby, limit potential axonal regeneration. This thesis investigates the effects of human adipose derived stem cells (ASC) on regeneration after peripheral nerve and spinal cord injury in adult rats. Human ASC expressed various neurotrophic molecules and growth factor stimulation of the cells in vitro resulted in increased secretion of BDNF, GDNF, VEGF-A and angiopoietin-1 proteins. Stimulated ASC also showed an enhanced ability to induce capillary-like tube formation in an in vitro angiogenesis assay. In contrast to Schwann cells, ASC did not induce activation of astrocytes and supported neurite outgrowth from the adult rat sensory DRG neurons in culture. In a peripheral nerve injury model, ASC were seeded into a fibrin conduit, which was used to bridge a 10 mm rat sciatic nerve gap. After 2 weeks, ASC enhanced GAP-43 and ATF-3 expression in the spinal cord, reduced c-jun expression in the DRG and increased the vascularity of the fibrin nerve conduits. The animals treated with stimulated ASC showed an enhanced axon regeneration and reduced caspase-3 expression in the DRG. After transplantation into the injured C3-C4 cervical spinal cord. ASC continued to express neurotrophic factors and laminin and stimulated extensive ingrowths of 5HT-positive raphaespinal axons into the trauma zone. In addition, ASC induced sprouting of raphaespinal terminals in C2 contralateral ventral horn and C6 ventral horn on both sides. Transplanted cells also changed the structure and the density of the astroglial scar. Although the transplanted cells had no effect on the density of capillaries around the lesion site, the reactivity of OX42-positive microglial cells was markedly reduced.

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37

Chen, Lin Min. "Angiogenic activities of Drynaria fortunei-derived extract and isolated compounds on zebrafish in vivo and human umbilical vein endothelial cells in vitro". Thesis, University of Macau, 2017. http://umaclib3.umac.mo/record=b3690926.

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38

Pons, Maria J., Cláudia Gomes, Ruth Aguilar, Diana Barrios, Miguel Angel Aguilar-Luis, Joaquim Ruiz, Carlota Dobaño, Valle-Mendoza Juana del y Gemma Moncunill. "Immunosuppressive and angiogenic cytokine profile associated with Bartonella bacilliformis infection in post-outbreak and endemic areas of Carrion's disease in Peru". Public Library of Science, 2017. http://hdl.handle.net/10757/622210.

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Analysis of immune responses in Bartonella bacilliformis carriers are needed to understand acquisition of immunity to Carrion’s disease and may allow identifying biomarkers associated with bacterial infection and disease phases. Serum samples from 144 healthy subjects from 5 villages in the North of Peru collected in 2014 were analyzed. Four villages had a Carrion’s disease outbreak in 2013, and the other is a traditionally endemic area. Thirty cytokines, chemokines and growth factors were determined in sera by fluorescent bead-based quantitative suspension array technology, and analyzed in relation to available data on bacteremia quantified by RT-PCR, and IgM and IgG levels measured by ELISA against B. bacilliformis lysates. The presence of bacteremia was associated with low concentrations of HGF (p = 0.005), IL-15 (p = 0.002), IL-6 (p = 0.05), IP-10 (p = 0.008), MIG (p = 0.03) and MIP-1α (p = 0.03). In multi-marker analysis, the same and further TH1-related and pro-inflammatory biomarkers were inversely associated with infection, whereas angiogenic chemokines and IL-10 were positively associated. Only EGF and eotaxin showed a moderate positive correlation with bacteremia. IgM seropositivity, which reflects a recent acute infection, was associated with lower levels of eotaxin (p = 0.05), IL-6 (p = 0.001), and VEGF (p = 0.03). Only GM-CSF and IL-10 concentrations were positively associated with higher levels of IgM (p = 0.01 and p = 0.007). Additionally, IgG seropositivity and levels were associated with high levels of angiogenic markers VEGF (p = 0.047) and eotaxin (p = 0.006), respectively. Our findings suggest that B. bacilliformis infection causes immunosuppression, led in part by overproduction of IL-10. This immunosuppression probably contributes to the chronicity of asymptomatic infections favoring B. bacilliformis persistence in the host, allowing the subsequent transmission to the vector. In addition, angiogenic markers associated with bacteremia and IgG levels may be related to the induction of endothelial cell proliferation in cutaneous lesions during chronic infections, being possible candidate biomarkers of asymptomatic infections.

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39

Möller, Björn. "Human Endometrial Angiogenesis : An Immunohistochemical Study of the Endometrial Expression of Angiogenic Growth Factors and Their Corresponding Receptors". Doctoral thesis, Uppsala University, Department of Women's and Children's Health, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3900.

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The human endometrium undergoes dramatic changes in morphology and function during the menstrual cycle. Recurrent angiogenesis (the formation of new blood vessels) is of utmost importance for oxygen supply and nourishment of the rapidly growing endometrial tissue.

The importance of some growth factors known to stimulate new blood vessel formation both in vivo and in vitro in non-uterine tissues, for endometrial angiogenesis, was studied. Further, the possible relationship between the patterns of expression of some angiogenic growth factors and bleeding disturbances during the use of a progestin-only intrauterine contraceptive device was analyzed. Different ways of determining changes in the endometrial vascular density during the menstrual cycle were also evaluated.

The expression of the angiogenic growth factors vascular endothelial growth factors (VEGF) A, B, C, and D, fibroblast growth factor 2 (FGF-2), and epidermal growth factor (EGF) and their receptors was analyzed using immunohistochemistry.

VEGF-A, -B and -C, FGF-2 and EGF and their receptors were all found to be expressed in normal human endometrium, especially in and/or around blood vessels, supporting the hypothesis that these peptides most probably contribute to the regulation of angiogenesis and blood vessel function in normal human endometrium.

There were differences in expression of some of the studied ligands and receptors in endometrium from users of an LNG-IUS with and without bleeding disturbances. We conclude that changes in the expression of these growth factors and receptors might be involved in the formation of fragile and dysfunctional blood vessels that subsequently give rise to bleeding disturbances.

The three different methods that were applied for calculating endometrial blood vessel density showed similar results and none of them indicated any significant changes during the menstrual cycle. Angiogenesis thus seems to occur mainly by blood vessel elongation and the angiogenic activity is probably related to changes in endometrial thickness and coiling of the spiral arteries.

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40

Haidar, Mariam [Verfasser] y Frauke von [Akademischer Betreuer] Versen-Höynck. "Vitamin D improves the angiogenic properties of endothelial progenitor cells / Mariam Haidar. Klinik für Frauenheilkunde und Geburtshilfe der Medizinischen Hochschule Hannover. Betreuer: Frauke von Versen-Höynck". Hannover : Bibliothek der Medizinischen Hochschule Hannover, 2014. http://d-nb.info/106067632X/34.

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41

Descamps, Betty. "Etude des propriétés angiogéniques du système Wnt/Frizzled : implication du récepteur Frizzled 4 dans la morphogénèse artérielle". Thesis, Bordeaux 2, 2009. http://www.theses.fr/2009BOR21670/document.

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De plus en plus d’études impliquent la signalisation Wnt/Frizzled (Wnt/Fzd) dans la formation des vaisseaux. La première partie de ce manuscrit démontre d’ailleurs que la signalisation Wnt, via son régulateur sFRP1 et un de ses ligands, Wnt4, potentialise les effets angiogéniques des cellules souches mésenchymateuses lors de l’angiogénèse. Le récepteur Frizzled4 (Fzd4), lui, est impliqué dans le développement vasculaire de la rétine puisque la délétion du gène fzd4 révèle une malformation du réseau vasculaire rétinien secondaire et tertiaire. Le but de ce travail a été d’étudier l’implication de Fzd4 dans la régulation de la morphogenèse vasculaire chez l’adulte. Il s’avère que Fzd4 présente un profil d’expression plutôt artériel, et que la délétion de ce gène empêche la formation d’un réseau artériel normal des organes périphériques. Des études in vitro réalisées sur des cellules vasculaires primaires ont mis en évidence plusieurs altérations de leurs propriétés angiogéniques. Cette étude a donc démontré un rôle central de Fzd4 dans la croissance vasculaire. Fzd4 régule les propriétés des cellules vasculaires mises en jeu dans l’angiogenèse, et régule la morphogenèse des ramifications vasculaires in vivo. Pour identifier et comprendre les mécanismes moléculaires induits par le récepteur Fzd4, une étude sur la protéine centrale du système Wnt/Fzd, l’isoforme Dishevelled (Dvl), et sur ses partenaires intracellulaires, a été initiée. Les premiers résultats suggèrent que les isoformes 1 et 3 de Dvl participent via Fzd4 à l’activation de la voie canonique nécessaire à la prolifération cellulaire. De plus, certains partenaires intracellulaires de Dvl3 ont pu être sélectionnés par une méthode de double hybride réalisée chez la levure
Growing evidences link Wnt/Frizzled (Wnt/Fzd) pathway to proper vascular formation. The first part of this manuscript shows besides that Wnt pathway, via its regulator sFRP1 and one of its ligands, Wnt4, potentiates mesenchymal stem cells angiogenic properties during angiogenesis. An other Frizzled receptor (Fzd), Fzd4, has been shown to be implicated in retinal vascular formation because inactivation of the fzd4 gene revealed a malformation of the secondary and tertiary retinal vascular network. Here, we investigated the involvement of Fzd4 in adult vascular morphogenesis regulation. Fzd4 present an arterial vascular pattern, and the deletion of fzd4 impairs a normal arterial network formation in peripheral organs. In vitro studies on primary vascular cells show several alterations on their angiogenic properties. This study reveals a central role of Fzd4 in vascular growth. Fzd4 regulate angiogenic vascular cell properties and vascular branching morphogenesis in vivo. To further understand molecular mechanisms induced by Fzd4, we started to study the Wnt/Fzd central protein, Dishevelled (Dvl), and its intracellular partners. First results suggest that Dvl 1 and 3 isoforms would participate with Fzd4 to activate Wnt canonical pathway implicated in cell proliferation. Moreover, some Dvl3 partners could be selected by a yeast two-hybrid method

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42

O'Rourke, Fiona [Verfasser], Ingo [Akademischer Betreuer] Ebersberger, Eckhard [Akademischer Betreuer] Boles, Volker [Akademischer Betreuer] Müller y Volkhard A. J. [Akademischer Betreuer] Kempf. "Interactions of Bartonella henselae with myeloid angiogenic cells and consequences for pathological angiogenesis / Fiona O'Rourke. Betreuer: Ingo Ebersberger ; Eckhard Boles. Gutachter: Volker Müller ; Volkhard A. J. Kempf". Frankfurt am Main : Univ.-Bibliothek Frankfurt am Main, 2015. http://d-nb.info/1080033920/34.

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43

Al-Delfi, Ibtesam. "The potential application of canine and human mesenchymal stem cells for the treatment of spinal cord injury : an in vitro examination of their neurotrophic and angiogenic activities". Thesis, Aston University, 2017. http://publications.aston.ac.uk/33385/.

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Traumatic spinal cord injury (SCI) is a devastating event. It causes severe damage to the nervous tissue which can be associated with partial or complete loss of movement and sensation. Recent studies suggested that the benefits of stem cell transplants for SCI may not be restricted to cell restoration alone, e.g. to replace damaged neurons, but also may be due to their capacity to stimulate endogenous cells at wound sites through paracrine activity. Mesenchymal stem/stromal cells (MSCs), in particular, are thought to have anti-inflammatory, neuroprotective, neurotrophic and angiogenic effects and may thus reduce secondary damage and promote neuroregeneration and wound healing after their administration. Experimental studies of small rodent SCI models are currently being used to investigate the MSCs as a promising option for treatments that repair damaged neuronal tissue. However, translation to human patients is still a challenging step. Dogs represent a good large animal model as the causes of SCI in dogs occur naturally and traumatically, and because of the similar scale and heterogeneity of the lesions formed. Therefore, this study aimed to investigate and compare the effects of canine and human MSCs, focused on the effects of MSC conditioned medium (MSC CM) on neurogenesis and angiogenesis using established responder cell lines, i.e. SH-SY5Y neuronal cells and EA.hy926 endothelial cells. All of the MSCs were derived from adipose tissue, and CD271 was used to isolate subset populations from human MSCs. The study has demonstrated for the first time the potentially beneficial effects of canine MSC CM in promoting SH-SY5Y neurite outgrowth and cell proliferation, as well as EA.hy926 endothelial cell proliferation, cell migration and the formation of endothelial tubules. Further experimentation demonstrated that canine and human adipose-derived MSCs exhibited such neurotrophic and angiogenic effects to a similar extent. This may have important implications for the pre-clinical assessment of MSC paracrine activity in the development of cell transplantation protocols both for dogs and humans. Finally, the study compared the neurotrophic and angiogenic effects of MSC CM from selected subpopulations of human MSCs, i.e. CD271+ versus CD271- and plastic adherent MSCs; this was with a view to establishing whether a more homogeneous MSC population might differ in their paracrine activity. There was no significant difference in the neurogenic effects of these various secretomes; however, MSC CM from humanCD271+MSCs was found to be significantly less pro-angiogenic than human CD271- MSCsor non-selected human MSCs. In conclusion, the study supports the use of MSCs to treat naturally occurring SCI in dogs, and suggests that there is no evidence herein to support preselecting CD271+ cells.

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44

Vilsmaier, Theresa [Verfasser] y Udo [Akademischer Betreuer] Jeschke. "Influence of circulating tumour cells on the immune response of T-Lymphocytes and Angiogenic cytokines in sera of patients with the primary diagnosis of breast cancer before treatment / Theresa Vilsmaier ; Betreuer: Udo Jeschke". München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2019. http://d-nb.info/1192215427/34.

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45

Tang, Yubo [Verfasser], Maik Akademischer Betreuer] Stiehler, Angela [Akademischer Betreuer] Jacobi, Michael [Akademischer Betreuer] [Gelinsky y Klaus-Peter [Akademischer Betreuer] Günther. "Traditional Chinese Medicine extracts exert angiogenic and protective effects towards human endothelial progenitor cells: from cellular function to molecular pathway / Yubo Tang. Gutachter: Michael Gelinsky ; Klaus-Peter Günther. Betreuer: Maik Stiehler ; Angela Jacobi". Dresden : Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://d-nb.info/1068447044/34.

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46

Ding, Haixia. "Effet de la radiothérapie sur la libération de microvésicules tumorales par des cellules de glioblastome". Thesis, Université de Lorraine, 2014. http://www.theses.fr/2014LORR0197.

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Dans le glioblastome (GBM), la radiothérapie est un outil thérapeutique essentiel. Néanmoins, la récidive post-irradiation est quasiment inévitable, en raison de l’émergence d'une sous-population de cellules cancéreuses particulièrement radiorésistantes présentant une meilleure capacité proliférative, invasive et pro-angiogénique. Notre étude in vitro a cherché à déterminer comment les cellules cancéreuses survivantes à l’irradiation pouvaient affecter la fonction des cellules tumorales voisines et les cellules endothéliales non irradiées, en focalisant notre attention sur l’échange des signaux intercellulaires, à savoir, les facteurs solubles et les microvésicules tumorales (TMVs). La radiothérapie induit principalement un ralentissement de la prolifération des cellules de glioblastome (T98G et U87) et une mort cellulaire retardée (clonogénique) de 50-60%, sans engendrer d’apoptose. Grâce au suivi de la croissance cellulaire à long terme (via le système xCELLigence) et un test de blessure, nous avons confirmé que les cellules de glioblastome survivantes après irradiation libèrent des signaux qui peuvent modifier les fonctions de cellules endothéliales HUVEC et de cellules tumorales non-irradiées. Outre la sécrétion de certains facteurs solubles connus (VEGF, uPA), nous avons pu objectiver, en utilisant la microscopie électronique à balayage, le Nanoparticle Tracking Analysis (NTA), la libération de microvésicules tumorales (TMVs), dont la taille était globalement inférieure à 500 nm. Par NTA et cytométrie en flux, nous avons montré que cette libération de TMVs (exosome + "shedding vesicles"), peut être significativement stimulée par l’irradiation dans les 2 lignées, de façon temps-dépendant. D’après nos analyses protéomiques, les facteurs solubles tels que le VEGF ou l’IL-8, connus pour être des facteurs pro-angiogéniques, contribueraient plutôt à favoriser la survie, voire la prolifération, des cellules HUVEC, tandis que les TMVs libérées après irradiation, ont significativement modifié la capacité de migration des HUVEC et des cellules tumorales non-irradiées. Les propriétés pro-migratoires des TMVs pourraient en ce sens, contribuer aux processus de récidive dans les glioblastomes après irradiation
Radiation therapy is a major therapeutic tool for glioblastoma (GBM). However, the post-radiation recurrence is almost inevitable, due to the emergence of a subpopulation of radioresistant cancer cells with greater proliferative, invasive, and proangiogenic capacities. The objective of this study was to investigate in vitro how irradiated cancer cells affect the function of untreated neighboring tumor cells and endothelial cells, focusing on signals exchange initiated by irradiation, such as soluble factors and tumor microvesicles (TMVs). Radiotherapy has slowed down the proliferation of GBM cells (T98G, U87) and induced mitotic death of 50-60%, without significant apoptosis. Through long-term monitoring of cell growth (xCELLigence) and wound-healing assay, we have confirmed that surviving GBM cells after irradiation release signals that can change the functions of endothelial cells HUVEC and non-irradiated tumor cells. In addition to the secretion of known soluble factors (VEGF, uPA), we were able to show using scanning electron microscopy and the Nanoparticle Tracking Analysis (NTA), the release of tumor microvesicles (TMVS), whose size was generally less than 500 nm. By NTA and flow cytometry, we have shown that the release of TMVs (exosome + "shedding vesicles") can be significantly stimulated by irradiation in two lines, in a time-dependent manner. According to the proteomics analysis, soluble factors such as VEGF or IL-8, well known as pro-angiogenic factors, rather contribute to promote the survival or proliferation of HUVEC, while the released TMVs after irradiation, significantly altered the migration abilities of non-irradiated HUVEC and tumor cells. The pro-migratory properties of TMVs could thus contribute to glioblastoma recurrence after irradiation

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Agra, Isabela Karine Rodrigues. "Expressão de células natural killer e suas citocinas em gestações gemelares complicadas com pré-eclâmpsia". Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/5/5139/tde-12062018-130315/.

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OBJETIVOS: Comparar a expressão placentária de células natural killer deciduais (dNK), e a expressão sérica e placentária de suas citocinas reguladoras em gestações gemelares com pré-eclâmpsia (grupo pré-eclâmpsia, GPE) e sem comorbidades (grupo-controle, GC). MÉTODOS: Estudo transversal do tipo caso-controle, desenvolvido na Clínica Obstétrica do HC-FMUSP no período de julho de 2015 a junho de 2017. Foram obtidas amostras das regiões deciduais placentárias, para avaliação, por meio de técnica de imuno-histoquímica, da expressão de células dNK e suas interleucinas (IL) 10, 12 e 15, em pacientes que contemplaram os critérios de inclusão e concordaram em participar do estudo. Além disso, estas pacientes tiveram amostra sérica colhida no terceiro trimestre para dosagem de IL-10, IL-12 e IL-15 - por meio de kit comercial Milliplex®, que utiliza a tecnologia Luminex® xMAP®, da EMDMillipore (Merck Millipore Co., Alemanha) - e de fatores relacionados à angiogênese, como soluble fms-like tyrosine kinase-1 (sFlt-1) e placental growth factor (PlGF) - por meio de ensaio com imunoanalisador COBAS e411 (Roche Diagnostics, Alemanha). Os valores obtidos para as análises placentárias e séricas foram comparados entre o GPE e o GC, e a significância estatística estabelecida foi p < 0,05. RESULTADOS: Foram selecionadas 30 pacientes, sendo 20 no GC e 10 no GPE. Não se observaram diferenças significativas com relação às características maternas, gestacionais e de desfechos perinatais entre os dois grupos, exceto pela idade gestacional de início do pré-natal, menor no GPE (12,5 vs. 20,0 semanas, p = 0,015). Quanto à avaliação placentária, houve maior expressão de IL-15 no GPE (p = 0,001), e não houve diferença entre os grupos quanto à expressão placentária local de células dNK (p = 0,999), IL-10 (p = 0,063) e IL-12 (p = 0,135). Com relação às interleucinas séricas maternas, demonstrou-se aumento significativo nos níveis de IL-10 (22,7 vs. 11,9 pg/mL, p = 0,024) e IL-15 (15,9 vs. 7,4 pg/mL, p = 0,024) no GPE com relação ao GC, sem diferença entre os grupos para IL-12 (102,5 vs. 61,5 pg/mL, p = 0,373). A dosagem dos fatores relacionados à angiogênese demonstrou maiores níveis séricos maternos de sFlt-1 (15920 vs. 7978 pg/mL, p = 0,009) e da razão sFlt-1/PlGF (88,71 vs. 24,63, p = 0,002), e menores valores de PlGF (193,0 vs. 340,6 pg/mL, p = 0,036) no GPE. CONCLUSÃO: Observou-se maior concentração sérica materna tanto de fatores pró quanto anti-inflamatórios no GPE, quando comparado ao GC. Entretanto, não foram observadas diferenças entre os grupos quanto à expressão placentária de IL-10, importante fator anti-inflamatório. Estes achados podem sugerir que a tentativa sérica materna de equilibrar estas interleucinas não alcançou resposta localmente na placenta, contribuindo para o desenvolvimento da doença no GPE
OBJECTIVES: To compare the placental expression of decidual natural killer cells (dNK) and serum and placental expression of their regulatory cytokines in twin pregnancies with preeclampsia (preeclampsia group, PEG) and uncomplicated twin pregnancies (control group, CG). METHODS: This was a case-control study, developed in a tertiary referral center, from July 2015 to June 2017. Samples of the placental decidual region were obtained and analyzed by immunohistochemistry technique for the expression of dNK cells and interleukins (IL) 10, 12 and 15, in patients who met the inclusion criteria. In addition, maternal serum sample was collected in the third trimester for the dosage of IL-10, IL-12 and IL-15 - by means of a commercial Milliplex® kit using Luminex® xMAP® technology from EMDMillipore (Merck Millipore Co., Germany) - and angiogenesis factors, such as soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) - by COBAS e411 immunoassay (Roche Diagnostics, Germany). The values obtained for the placental analyzes and maternal circulating factors were compared between PEG and CG and the statistical significance was set at p < 0.05. RESULTS: Thirty patients were selected, 20 in CG and 10 in PEG. There were no significant differences in maternal, gestational and perinatal outcomes between the two groups, except for the gestational age at the onset of prenatal care, which was lower in PEG (12.5 vs. 20.0 weeks, p = 0.015). PEG showed strong immunostaining for IL-15 (p = 0.001) when compared to CG, with no difference between the groups concerning the placental expression of dNK (p = 0.999), IL-10 (p = 0.063), and IL -12 (p = 0.135). Relating to maternal circulating interleukins, a significant increase in IL-10 (22.7 vs. 11.9 pg/mL, p = 0.024) and IL-15 (15.9 vs. 7.4 pg/mL, p = 0.024) was observed in PEG, with no difference between the groups for IL-12 (102.5 vs 61.5 pg/mL, p = 0.373). We also demonstrated higher maternal levels of sFlt-1 (15920 vs. 7978 pg/mL, p = 0.009) and sFlt-1/PlGF ratio (88.71 vs. 24.63, p = 0.002) and lower levels of PlGF (193 vs. 340.6 pg/mL, p = 0.036) in PEG. CONCLUSION: A higher maternal serum concentration of both pro- and anti-inflammatory factors was observed in the PEG. However, no difference was found between the groups regarding the placental expression of IL-10, an important anti-inflammatory factor. These findings may suggest that the maternal serum attempt to balance these interleukins did not reach local placental response, which contribute to the development of the disease in the PEG

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Farrar, Charlotte Elizabeth. "Molecular regulation of angiogenesis by protese-activated receptors (PARS): differential utilisaton of cyclooxygenase-2 and peroxisome proliferator-activated receptor". Thesis, Royal Veterinary College (University of London), 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.618320.

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Pimentel, Thaís Valéria Costa de Andrade. "Influência de fatores de crescimento pró-angiogênicos na manutenção das características de células progenitoras mesenquimais derivadas do tecido adiposo". Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/17/17153/tde-02022016-100332/.

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A manutenção do estado progenitor durante o cultivo de células mesenquimais progenitoras derivadas do tecido adiposo (MSCs-TA), caracterizado pelo potencial de diferenciação e da capacidade de autorrenovação, é atualmente um dos maiores desafios da terapia celular. Sabendo da influência da angiogênese no desenvolvimento de tecidos de origem mesenquimal, avaliamos se um ambiente pro-angiogênico mimetizado em cultura forneceria condições para manutenção de um estado progenitor durante o processo de expansão celular. Utilizando como modelo de um ambiente pró-angiogênico o cultivo no meio EGM-2, o qual é suplementado pelos fatores de crescimento EGF, FGF-2, IGF e VEGF, nós demonstramos que a presença de tais fatores pró-angiogênicos é fundamental para a manutenção do estado progenitor de MSCs-TA em cultura. Verificamos que a presença de tais fatores de crescimento possibilitaram às MSCs-TA apresentarem um alto potencial de diferenciação adipogênico e osteogênico em comparação ao meio convencional DMEM/F12 e ao meio EBM, ausente de fatores. Além disso, o cultivo na presença de fatores pró-angiogênicos aumentou o potencial clonogênico das MSCs-TA, ao mesmo tempo em que aumentou a capacidade proliferativa destas células. Dentre os fatores de crescimento, EGF e FGF-2 foram responsáveis pelos efeitos mais robustos. Ao mesmo tempo, células cultivadas nas presença destas citocinas foram capazes de manter a morfologia fibroblastóide e apresentaram alta expressão do fator de pluripotência Klf-4. Em concordância com estes achados, o transplante subcutâneo de MSCs-TA cultivadas nestas condições mostrou que aquelas mantidas em EGM-2 geram um tecido semelhante ao tecido formado pela fração estromal vascular não cultivada. Estes resultados reforçam o papel do ambiente pró-angiogênico na manutenção do estado progenitor de MSCs-TA, e que tal estado foi proporcionado pela ação dos fatores de crescimento pró-angiogênicos EGF, FGF-2, IGF e VEGF nas células em cultivo, com destaque para as citocinas EGF e FGF-2. Em conclusão, o uso do ambiente pró-angiogênico no cultivo de MSCs-TA mostrou-se como uma abordagem promissora para a manutenção do estado progenitor destas células in vitro.
The maintenance of the progenitor state in the culture of adipose tissue derived- mesenchymal progenitor cell (TA-MSCs), characterized by the differentiation potential and self-renewal capability, is currently one of the major challenges of cell therapy. The information that the angiogenesis influences the development of mesenchymal tissues, has led us to evaluate how a pro-angiogenic environment mimicked in culture would provide conditions for maintaining a progenitor state during the cell expansion process. We designe a model for a pro-angiogenic environment in which cells grown in EGM-2 supplemented with the following growth factors: EGF, FGF-2, IGF and VEGF, and demonstrated that the presence of such pro-angiogenic growth factors was crucial for maintenance of the progenitor of AT-MSCs in culture. We observed that the presence of such growth factors allowed to AT-MSCs a high potential of adipogenic and osteogenic differentiation compared to conventional DMEM/F12 medium and the EBM medium, in the absence of the factors. Furthermore, the culture in presence of pro-angiogenic growth factors increased the clonogenic potential of AT-MSCs and increased the proliferative capability of these cells. Among the growth factors, EGF and FGF-2 were responsible for most robust effects. At the same time, cells cultured in the presence of these cytokines were able to maintaining the fibroblastoid morphology and presented high expression levels of Klf-4 pluripotency factor. In agreement with these observations, the subcutaneous transplantation of AT-MSCs cultured under these conditions showed that those cells kept in EGM-2 generated a tissue-like to tissue formed by the stromal vascular fraction uncultivated. These results reinforce the role of the pro-angiogenic environment in the maintenance of the progenitor state of AT-MSCs, and that such a state was provided by the action of the pro-angiogenic growth factors EGF, FGF-2, IGF and VEGF in cultured cells, highlighting EGF and FGF-2 cytokines. In conclusion, we showed that the use of a pro-angiogenic environment in AT-MSCs culture is a promising approach to the maintain the progenitor state of these cells in vitro.

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50

Taylor-Marchetti, Melissa. "Cellules endothéliales circulantes et progéniteurs endothéliaux circulants : biomarqueurs de l'angiogénèse tumorale et des traitements anti-angiogéniques et anti-vasculaires". Phd thesis, Université Paris Sud - Paris XI, 2012. http://tel.archives-ouvertes.fr/tel-00794880.

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Malgré l'efficacité thérapeutique avérée des agents anti-angiogéniques et des agents anti-vasculaires (VDA), le mécanisme d'action précis des stratégies ciblant les vaisseaux sanguins tumoraux, les raisons de leur efficacité ainsi que les mécanismes de résistance à ces drogues sont encore mal compris. Il est rapidement apparu essentiel d'identifier des biomarqueurs capables de refléter l'angiogénèse tumorale ou les effets sur la vascularisation tumorale de ces traitements. Compte tenu de leur importance dans des pathologies vasculaires, les cellules endothéliales matures circulantes (CEC) et les progéniteurs endothéliaux circulants (CEP) ont d'emblée été pressenties comme des candidats intéressants pour être des biomarqueurs de réponse aux stratégies ciblant la vascularisation tumorale. Nous avons exploré l'intérêt de ces cellules en tant que biomarqueurs de l'angiogénèse dans des tumeurs pédiatriques, et leur rôle en tant que biomarqueurs de traitement par des agents anti-angiogéniques chez des sujets adultes atteints de cancer. Ces travaux ont mis en lumière l'intérêt des CEP et ont été à la source d'un travail plus " mécanistique " où nous avons étudié dans différents modèles murins le rôle des CEC et CEP dans le mécanisme d'action des agents anti-vasculaires et plus particulièrement le rôle fonctionnel des CEP dans la résistance à ces molécules. Par des stratégies d'association d'agents anti-angiogéniques aux VDA destinées à inhiber les CEP, nous montrons l'augmentation de l'activité anti-tumorale des VDA et offrons un rationnel mécanistique pour optimiser les schémas thérapeutiques actuels des traitements anti-vasculaires. Nos données apportent des arguments en faveur du rôle potentiel de ces cellules en tant que biomarqueurs de l'angiogénèse, des traitements anti-angiogéniques et de la résistance aux traitements anti-vasculaires.

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