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1
Meadows, Kafi, Seema Iyer, Mark Stevens, Duanning Wang, Sharon Shechter, Carole Perruzzi, Todd Camenisch, and Laura Benjamin. "Akt promotes Endocardial-Mesenchyme Transition." BioMed Central, 2009. http://hdl.handle.net/10150/610167.
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Endothelial to mesenchyme transition (EndMT) can be observed during the formation of endocardial cushions from the endocardium, the endothelial lining of the atrioventricular canal (AVC), of the developing heart at embryonic day 9.5 (E9.5). Many regulators of the process have been identifiedhowever, the mechanisms driving the initial commitment decision of endothelial cells to EndMT have been difficult to separate from processes required for mesenchymal proliferation and migration. We have several lines of evidence that suggest a central role for Akt signaling in committing endothelial cells to enter EndMT. Akt1 mRNA was restricted to the endocardium of endocardial cushions while they were forming. The PI3K/Akt signaling pathway is necessary for mesenchyme outgrowth, as sprouting was inhibited in AVC explant cultures treated with the PI3K inhibitor LY294002. Furthermore, endothelial marker, VE-cadherin, was downregulated and mesenchyme markers, N-cadherin and Snail, were induced in response to expression of a constitutively active form of Akt1 (myrAkt1) in endothelial cells. Finally, we isolated the function of Akt1 signaling in the commitment to the transition using a transgenic model where myrAkt1 was pulsed only in endocardial cells and turned off after EndMT initiation. In this way, we determined that increased Akt signaling in the endocardium drives EndMT and discounted its other functions in cushion mesenchymal cells.
2
Vujovic, Sonja. "Transcriptional profiling of mesenchymal stem cells, undergoing chondrogenesis, and mesenchymal tumours." Thesis, University College London (University of London), 2006. http://discovery.ucl.ac.uk/1445141/.
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Mesenchymal stem cells (MSC) represent an adult stem cell population isolated from the bone marrow with the ability to differentiate down various mesenchymal lineages including cartilage. The development of cartilage is a complex multiphase process regulated by the interplay of factors such as cell density and oxygen availability as well as many signalling pathways including TGFp, MAPK, FGF and Wnt. Using microarrays, the temporal transcriptional changes occurring in the in vitro MSC chondrogenesis model were analysed. The results obtained support the validity of the MSC model system for the study of chondrogenesis, as genes known to play a role in the process such as collagens 2, 9 and 11, aggrecan and the transcription factor Sox9, are expressed in the chronological pattern expected. Genes were also identified that had been previously noted to be expressed in limb development but whose role in chondrogenesis remains unknown, as well as a group of novel factors not previously associated with chondrogenesis. Hes1 and Hey1, the targets of Notch signalling were both found to be upregulated early, and their role in chondrogenesis was investigated by inhibiting Notch signalling. Abolishing the expression of Hes1 and Hey1 had a deleterious effect on the accumulation of the chondrogenic matrix, indicating that these transcription factors are implicated in chondrogenesis. Microarray analysis was also used to compare the expression profiles of a broad range of mesenchymal tumours, resulting in the identification of factors specific to each. The brachyury gene was found to be specifically expressed on chordomas, a tumour derived from notochordal remnants often misdiagnosed for a chondrosarcoma. Immunohistochemistry was performed using a polyclonal antibody to this molecule and was found to distinguish chordomas from over 300 other lesions, including a wide variety of chondroid neoplasms. Brachyury is therefore a specific marker for chordomas, and can be exploited for diagnostic purposes.
3
Teague, Warwick J. "Mesenchyme-to-epithelial transition in pancreatic organogenesis." Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.670115.
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Suniara, Ravinder K. "The role of mesenchyme in early thymic development." Thesis, University of Birmingham, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.270080.
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Jayanthi, Naga Venkatesh Gupta. "The role of pancreatic mesenchyme in islet development." Thesis, University of Newcastle upon Tyne, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.437249.
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Wong, Yin-kwai, and 王現葵. "Characterization of hMSCs transmigrated through collagen barrier." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B47869720.
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Stem cell therapy is a promising approach for tissue regeneration but there exists a
problem of low engraftment rate to the injury site. Our laboratory has shown that
hMSCs that were capable to penetrate through collagen barrier have higher
migration capacity and engraftment efficiency than those remained inside the
collagen matrix and those in traditional 2D culture. These cells capable of
penetrating through collagen barrier might be hopeful candidate for improving
engraftment efficacy. Major processes of engraftment, such as transmigration
through basement membrane and invasion to the site of injury, involve
cell-extracellular matrix-interacting proteins. As matrix metalloproteinases (MMP)
and integrins are the key players in these processes, MMP and integrin profiles of
the hMSCs were studied
In this study, we demonstrated that hMSCs that were capable of penetrating
through the collagen barrier have distinctive MMP profile to traditional 2D culture.
These cells secrete significantly higher amount of MMP-1 than 2D culture, but the
amount of MMP-2 secreted is comparable to traditional 2D culture. On the other
hand, MMP-9 and MMP-13 were below detection limit by ELISA in both groups.
Moreover, we have investigated the subcellular localization of MMPs and
integrins. The cells were seeded on dishes with or without ECM coatings. It was
demonstrated that hMSCs capable of penetrating through collagen barrier exhibit
higher amount of subcellular MT1-MMP and integrin 6271 on ECM coated dish.
Moreover, these cells exhibit a prominent feature of perinuclear localization of
MT1-MMP., whereas the level of subcellular MMP-2, integrin 65 and 6v73 is
comparable to that in 2D culture.
We have also investigated the stem properties of hMSCs penetrated through
collagen barrier. These properties include proliferation capacity, self-renewal
capacity and differentiation potential towards chondrogenic, osteogenic and
adipogenic lineages. It has been demonstrated that these properties are not
compromised for superior migratory activities.published_or_final_version
Mechanical Engineering
Master
Master of Philosophy
7
Karystinou, Alexandra. "YAP in mesenchymal stem cells." Thesis, University of Aberdeen, 2012. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=192255.
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MSCs are the most studied subtype of adult stem cells and have been derived from most postnatal organs and tissues. MSCs are defined as having the capacity to self-renew and to differentiate into both mesodermal and non-mesodermal lineages, and are immunosuppressive. For these properties, MSCs have been considered ideal candidates for regenerative medicine and have been used in several clinical trials. The difficulty, however, to preserve the potency of the cells during culture expansion and to monitor differentiation are obstacles in their use in the clinic and have emphasized the need to investigate molecular pathways underlying stem cell fate-decisions during differentiation in more detail. Hippo pathway was recently identified in Drosophila melanogaster and mammals, and controls organ size by regulating cell proliferation, apoptosis and differentiation. It is composed of a core of serine/threonine kinases and scaffold proteins that when activated, phosphorylate and inhibit yes-associated protein (YAP) transcriptional co-factor. Inactivation of YAP in some stem and progenitor cells by this pathway is required for their differentiation. In contrast, failure to inhibit YAP enhances proliferation and may cause oncogenic transformation. In the present study, the expression of multiple YAP variants was confirmed in human and mouse MSCs. In both human and mouse, YAP was inhibited in response to cell-contact inhibition and remained unchanged during in vitro chondrogenic differentiation. Overexpression of human (hYAP1) variant in C3H/10T1/2 cells did not appear to affect colony formation, cell cycle distribution or cell size, but increased cell proliferation, induced cell transformation and reduced the in vitro differentiation capacity of the cells towards the chondrogenic, adipogenic and osteogenic lineages. The effects of hYAP1 overexpression are hypothesized to be either a result of a nuclear co-factor function or indirectly via protein interactions in the cytoplasmic compartment. Hippo pathway and YAP are possible pharmacological targets for modulation of MSC function.
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Hahnel, Mark. "Trafficking of mesenchymal stem cells." Thesis, Imperial College London, 2012. http://hdl.handle.net/10044/1/14559.
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In adult life mesenchymal stem cells (MSCs) reside primarily in the bone marrow and are defined according to their ability to self-renew and differentiate into tissues of mesodermal origin. Due to their immuno-modulatory properties and ability to form cartilage and bone, MSCs have clinical potential, for the treatment of autoimmune diseases and tissue repair. This project determines the chemokine receptor profile on murine bone marrow MSCs at early and late passage and on human MSCs derived from a range of fetal tissues including fetal blood, bone marrow, amniotic fluid and placenta. The overwhelming result from this analysis is the consistency across species and tissue source with respect to chemokine receptor profiles. In addition it is clear that expression of specific chemokine receptors defines sub-populations of MSCs. Currently, clinical trials using MSCs have relied on continued in vitro culture in order to obtain sufficient numbers for treatment. Here, MSCs have been shown to lose external chemokine receptor expression and associated chemotactic ability, whilst growing in size upon continued culture. All cultured MSCs investigated in this thesis were shown to be a heterogeneous population of stem cells and progenitors that contained ‘true’ MSCs within its number. This thesis investigates a pharmacological approach to mobilise endogenous MSCs from the bone marrow, increasing their numbers in the blood. It has previously been reported that administration of VEGF-A over 4 days followed by a single dose with a CXCR4 antagonist (AMD3100) causes selective mobilisation of MSCs into blood. The VEGF biology of this response has been interrogated. MSCs were shown to express high levels of VEGFR-1 and lower levels of VEGFR-2 on the cell surface but do not express VEGFR-3. By blocking VEGFR-1 with mAbs during VEGF-A165 treatment, a ten-fold increase in MSC mobilisation in response to AMD3100 was recorded, while treating with VEGFR-2 blocking mAbs had no effect. Using VEGF isoforms specific for VEGFR-1 and VEGFR-2 (PlGF and VEGF-E respectively), it was determined that MSC mobilisation was dependant on activation of VEGFR-2 and not VEGFR-1. PαS cells are a subset of MSCs found in the murine bone marrow that are PDGFRα+, Sca-1+, CD45-, Ter119-. Further characterisation of mobilised mMSCs by flow cytometric analysis of PαS cells, now provides a way to investigate the biology of MSCs, both in their steady state in vivo and in models of injury and inflammation. Molecular mechanisms lying downstream of VEGFR-2 have been explored and it has been shown that MMPs play a critical role in mobilisation. The use of drugs to mobilise MSCs into the blood may provide a cost effective, non-invasive treatment to promote tissue repair.
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De, Arpan. "Circadian clock regulation of epithelial-mesenchymal and mesenchymal-epithelial transitions in glioma and breast cancer cells." Bowling Green State University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1566494866910786.
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陳德華 and Tak-wah Chan. "Epithelial-mesenchymal interactions in development and cytodifferentiation of seminal vesicle." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1994. http://hub.hku.hk/bib/B31211239.
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譚毅忠 and Ngai-chung Neville Tam. "The influence of embryonic urogenital sinus mesenchyme on the cytodifferentiation of the dunning prostatic adenocarcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1995. http://hub.hku.hk/bib/B31213625.
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Wong, Chu-hei, and 黃曙曦. "Effects of anoikis stress on human mesenchymal stem cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B41633775.
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Chan, Tak-wah. "Epithelial-mesenchymal interactions in development and cytodifferentiation of seminal vesicle /." Hong Kong : University of Hong Kong, 1994. http://sunzi.lib.hku.hk/hkuto/record.jsp?B13762692.
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Tam, Ngai-chung Neville. "The influence of embryonic urogenital sinus mesenchyme on the cytodifferentiation of the dunning prostatic adenocarcinoma /." Hong Kong : University of Hong Kong, 1995. http://sunzi.lib.hku.hk/hkuto/record.jsp?B16504793.
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Wong, Chu-hei. "Effects of anoikis stress on human mesenchymal stem cells." Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B41633775.
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Jussila, T. (Tommi). "Modelling cancer: recapitulation of tumor growth in experimental systems in vivo and in vitro." Doctoral thesis, University of Oulu, 2000. http://urn.fi/urn:isbn:9514256433.
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Abstract
The purpose of the study was to evaluate model systems of cancer development and
compare some of their critical features with cancer development in
vivo. Ovarian and endometrial cancers in man were used as correlates.
Tumor development in experimental animals, exposed to carcinogens and UV
irradiation, showed the entire spectrum of tumor development as compared to
spontaneous carcinomas: hyperplasia, dysplasia, benign papillomas and malignant
squamous cell carcinomas. For short-term analysis of differentiated homogenous
cell populations, the transplant model proved most useful. For long term
analysis of effects of extraneous agents, the skin carcinogenesis model is
probably the most rewarding.
Analysis of proliferation markers in human tumor samples as studied by
immunohistochemistry, showed that an increased expression of PCNA and Ki-67 was
associated with poor prognosis in ovarian neoplasms. Analysis of cell
proliferation in model tumors showed that the transplant model has a better
sensitivity when compared to the animal skin model and the subcutaneous
injection model, in that effect of changes in cell-host interaction on the
location and extent of the proliferating cell population can be studied therein.
The expression of some growth factors, their receptors, oncogenes and suppressor
genes were studied in ovarian and endometrial carcinomas and in skin cancer
model system in mouse exposed to carcinogens and UV irradiation. Variability in
expression and methodological problems precluded detailed analysis of these
markers in different models.
The expression of TGFβ1, TGFβ2 and TGFβ3 was determined in normal
human keratinocytes, and in 7 immortalized and
ras-transfected benign and malignant keratinocyte cell
lines, maintained as transplants and as subcutaneous tumors in nude mice. By
differential immunohistochemical localization of TGFβ isoforms, we
demonstrated that each isoform may serve specific roles in tumor development and
progression. The complex nature of TGFβ expression prevented detailed
analysis of isozymes in different models, the results in this study, however,
indicated a similar pattern in the models analyzed.
Morphological methods were used to determine relationship between epithelial
growth and formation and deposition of collagens in the extracellular matrix in
experimental models and human tumors. The composition of the mesenchyme differed
in tumors originating from different cell lines reflecting functional
interaction between epithelial cells and the mesenchyme in neoplastic
development. Tumor-stroma interaction was distinct in human, comparable
alterations were observed in experimental models, more so in transplants, less
in subcutaneous tumors, affecting tumor growth and differentiation in the
different models.
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Gaboury, Louis A. "Studies of the role of mesenchymal cells in the regulation of hemopoiesis." Thesis, University of British Columbia, 1988. http://hdl.handle.net/2429/28784.
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Hemopoiesis is thought to be regulated in part by specific, but as yet undefined, interactions between primitive hemopoietic cells and fixed, non-hemopoietic marrow elements collectively referred to as the stroma. Recently, a marrow culture system has been described that allows the maintenance of primitive human hemopoietic progenitor cells for many weeks in the absence of exogenously added hemopoietic growth factors. The formation of a heterogeneous adherent layer in which many stromal elements are found appears to be important to the maintenance of hemopoiesis in this system. As part of the overall goal of delineating the cellular and molecular interactions involved, my first objective was to develop an experimental system for assessing the hemopoiesis-sustaining function of the adherent layer of long-term human marrow cultures. This required the identification of a suitable procedure for separating the hemopoietic and non-hemopoietic regulatory components so that the former could be used to quantitate the function of the latter. This was achieved using irradiation to selectively inactivate residual hemopoietic cells in long-term culture adherent layers, and using a medium containing cis-4-hydroxy-L-proline to selectively inactivate stromal cells and their precursors present in suspensions of unseparated human marrow which were then added back in co-culture experiments.
My second objective was to develop a strategy for obtaining purified populations of cells corresponding to the various mesenchymal cell types in long-term adherent layers. I therefore prepared a high titre SV-40 virus stock and used it to establish permanent, cloned lines from human marrow "fibroblast" colonies, long-term culture adherent layers, and umbilical cord endothelial cells. Characterization of the transformants generated showed that they were all positive for SV-40, and in general expressed the phenotypic characteristics of the cells originally infected. Functional studies showed that these transformants, like their normal counterparts, respond to activation by producing two types of hemopoietic growth factors.
These studies suggest that marrow mesenchymal cells may regulate the growth and maintenance of primitive hemopoietic cells by producing hemopoietic growth factors in response to appropriate perturbation. The availability of permanent cloned lines of human marrow stromal cells should facilitate future analysis of these events at the molecular level.Medicine, Faculty of
Pathology and Laboratory Medicine, Department of
Graduate
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Lemieux, Justin Michael. "Mechanisms of Hematopoietic-Mesenchymal Cell Activation." Yale University, 2009. http://ymtdl.med.yale.edu/theses/available/etd-03112009-191829/.
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As the prevalence of osteoporosis is expected to increase over the next few decades, the development of novel therapeutic strategies to combat this disorder becomes clinically imperative. These efforts draw extensively from an expanding body of knowledge pertaining to the physiologic mechanisms of skeletal homeostasis. To this body of knowledge, we contribute that cells of hematopoietic lineage may play a crucial role in balancing osteoblastic bone formation against osteoclastic resorption. Specifically, our laboratory has previously demonstrated that megakaryocytes can induce osteoblast proliferation in vitro, but do so only when direct cell-to-cell contact is permitted. To further investigate the nature of this interaction, we have effectively neutralized several adhesion molecules known to function in the analogous interaction of megakaryocytes with another cell-type of mesenchymal origin - the fibroblast. Our findings implicate the involvement of fibronectin/RGD-binding integrins including á3â1 (VLA-3) and á5â1 (VLA-5) as well as glycoprotein IIb (CD41), all of which are known to be expressed on megakaryocyte membranes. Furthermore, we demonstrate that IL-3 can enhance megakaryocyte-induced osteoblast activation in vitro, as demonstrated in the megakaryocyte-fibroblast model system. Taken together, these results suggest that although their physiologic and clinical implications are very different, these two models of hematopoietic-mesenchymal cell activation are mechanistically analogous.
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Kosinski, Cynthia. "Epithelial-mesenchymal interactions in intestinal development." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2009. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3390108.
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Rasmusson, Ida. "Immune modulation by mesenchymal stem cells /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-384-1/.
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Ackema, K. B. "Hox genes and mesenchymal stem cells." [S.l.] : Rotterdam : [The Author] ; Erasmus University [Host], 2008.
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Dennis, James Edmund. "Mesenchymal progenitor cells in adult marrow." Case Western Reserve University School of Graduate Studies / OhioLINK, 1995. http://rave.ohiolink.edu/etdc/view?acc_num=case1062516436.
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Trento, Cristina. "Interaction between haematopoietic and mesenchymal stroma." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/37557.
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Parenchyma and stroma represent the functional and structural units in every organ of the body respectively. Stromal cells of mesenchymal origin (MSC) have traditionally been associated with a structural support activity within the tissue, but it is only recently that more complex functions have been unveiled. Subsets of MSC have been shown to play a fundamental role in self-renewal and differentiation of haematopoietic stem cells (HSC). Recent findings show that MSC and bone marrow (BM) macrophages represent fundamental components in the niche, modulating egress and mobilization of HSC during normal or emergency myelopoiesis. Therefore, I have decided to investigate whether and how MSC contribute to the formation and function of myeloid cells. In an in vitro co-culture model I have observed that MSC have the ability to induce the expansion and differentiation of different subsets of mature myeloid cells from haematopoietic BM cells. Based on the differential expression of CD11b and Gr-1, three cell subsets recapitulating myeloid differentiation could be identified. MSC induced differentiation targets common myeloid progenitors (CMP) or granulocyte/macrophage progenitors (GMP) but not the primitive HSC. CD11b+ sorted cells obtained at the end of the co-culture exhibited a functional profile characterised by high levels of both anti- and pro-inflammatory markers, such as nitric oxide synthase 2 (NOS2) and arginase-1 (ARG-1). In order to identify the mechanisms involved in this phenomenon I have chosen to investigate a number of molecules involved in the regulation of haematopoietic differentiation by the microenvironment. I have demonstrated that whilst NOS2 and agrin, an ECM protein, play a key role in the differentiation of CD11b+ Gr-1- F4/80+ cells, complement appears to be primarily involved in the generation of CD11b+ Gr-1int-low F4/80- cells. My studies have shown that MSC differentiating activity is not confined to the BM but can also be detected in MSC from other tissues like skin and kidney. Overall these results suggest a key role for stromal cells as regulators of myeloid differentiation. Further investigation is under way to assess the importance of such a function in vivo.
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Singh, Shailendra. "Characterisation of Mesenchyme-Derived Cell Populations in the Human Airways." Thesis, University of Nottingham, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.517789.
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Lin, Liwen. "Study of hydroxyapatite osteoinductivity with an osteogenic differentiation assay using mesenchymal stem cells /." View abstract or full-text, 2007. http://library.ust.hk/cgi/db/thesis.pl?BIEN%202007%20LIN.
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Au-yeung, Kwan-lok, and 歐陽君諾. "Effect of cyclic compressive loading on human mesenchymal stem cells (hMSCs) seeded in type I collagen matrix." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B41509031.
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Lu, Xiaofeng. "Changes in cytodifferentiation of the dunning prostatic adenocarcinoma induced by neonatal rat seminal vesicle mesenchyme /." Hong Kong : University of Hong Kong, 1998. http://sunzi.lib.hku.hk/hkuto/record.jsp?B19852216.
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Cheung, Pak-yan. "Esophageal carcinogenesis : immortalization, transformation and epithelial-mesenchymal transition /." Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B41290379.
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Au-yeung, Kwan-lok. "Effect of cyclic compressive loading on human mesenchymal stem cells (hMSCs) seeded in type I collagen matrix." Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B41509031.
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McHaffie, Sophie Louise. "Investigating the role of Wt1 in bone and marrow biology." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/17915.
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The bones of the body vary in size and shape, but are fundamentally all composed of the same cell types: osteoblasts, osteoclasts, osteocytes, vascular cells, and sometimes marrow cells. Long bones are formed when mesenchymal stem cells (MSCs) give rise to chondrocytes i.e. cartilage cells, and osteoblasts i.e. bone cells. These develop to form layers of bone encasing a cartilagenous core which eventually becomes the marrow cavity. A recent study showed that deleting the Wilms’ tumour gene, Wt1, in adult mice causes a dramatic loss of bone and fat tissue, fat being another derivative of MSCs. This finding led me to ask whether Wt1 expression is involved in bone biology and whether it plays a functional role in the stem or progenitor populations. Wt1 is a transcription factor that acts as a mesodermal / mesenchymal regulator. It acts as a tumour suppressor gene with mutations leading to the eponymous paediatric kidney tumour. However, in adult cancers it has oncogene characteristics, being highly expressed in the tumours of tissues in which it is not normally present. It also plays a pivotal role in the epithelial to mesenchymal transition (EMT) and vice versa in developing heart and kidney, respectively. There is, however, no evidence of its involvement with EMT / MET in adults. Wt1 is expressed in various developing tissues and is particularly vital for kidney development. Due to its involvement as a regulator of EMT / MET during development and the phenotype observed following its deletion in vivo, we hypothesised that Wt1 is expressed in, and required for the function of mesenchymal stem or progenitor cells populations within the bone marrow. A Wt1-GFP knock in mouse was used to show that Wt1 expressing cells are found in the bone marrow, and also for the first time in the bone. The GFP population overlaps with a non-haematopoietic MSC population defined by 3 cell surface markers in the bone and marrow, as well as an osteoblast (OB) progenitor population. Using a tamoxifen inducible CreERT2 showed that Wt1 loss alters the proportion of GFP cells in the bone and marrow cells that overlap with these MSC and OB progenitor markers, but microarrays were needed to assess the functional effects of Wt1 deletion. Microarrays highlighted various pathways that were altered following the in vitro deletion of Wt1 in total bone and marrow culture, as well as the non-haematopoeitic GFP+ and GFP- populations. In bone cells, deleting Wt1 negatively affects various pathways related to MSCs and their derivatives, including collagen biosynthesis, cartilage development and muscle tissue development. Also negatively affected were Wnt signalling regulation and EMT regulation; this is the first time Wt1 has been shown to be involved in EMT in adult cells. These findings were validated using qRT-PCR to show the down regulation of various genes involved in each pathway, showing that as well as being expressed in these populations it is also playing a functional role. Ossification pathways were negatively altered in the cells not expressing Wt1 following the deletion of the gene suggesting that Wt1 may also be acting in a paracrine manner to play its role in bone homeostasis. As well as in adult tissues, Wt1 was found to be expressed during development in the limb tissue of e11.5 to e16.5 mice. Preliminary results show that Wt1 may also have a functional role during bone development, as loss of expression causes a reduction in the percentage of non-haematopoetic MSC cells in the e18.5 hindlimb. As well as this, preliminary lineage tracing experiments suggest that cells found at the bone surface are of Wt1+ origin. This thesis has also highlighted the importance of experimental conditions and controls, particularly for CFU-F assays. CreERT2, loxP sites, tamoxifen, oxygen tension levels, and gender all exert specific effects on colony formation, independent of Wt1 expression. In conclusion, these data identify Wt1 as a key player in bone development and homeostasis. The microarray results led to the conclusion that Wt1 has a functional role in several mesenchymal pathways and highlights various genes that are potential Wt1 targets and should be further investigated using ChIP-Seq methods.
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Millanes, Romero Alba 1986. "Heterochromatin dynamics during epithelial-to-mesenchymal transition." Doctoral thesis, Universitat Pompeu Fabra, 2014. http://hdl.handle.net/10803/129339.
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Although heterochromatin is enriched with repressive traits, it is actively transcribed, giving
rise to large amounts of non-coding RNAs. These transcripts are responsible for the formation
and maintenance of heterochromatin, but little is known about how their transcription is
regulated. In this thesis we show that Snail1 transcription factor represses mouse
pericentromeric transcription and regulates heterochromatin organization through the action
of the H3K4 deaminase LOXL2. Snail1 has a key role in epithelial-to-mesenchymal transition
(EMT). We show that, also during this process, Snail1 is responsible for pericentromeric
transcription regulation. At the onset of EMT, one of the major structural heterochromatin
proteins, HP1α, is transiently released from heterochromatin foci in a Snail1/LOXL2 dependent
manner, concomitantly with a down-regulation of major satellite transcription. Moreover,
prevention of major satellite transcripts down-regulation compromises the migratory and
invasive behaviour of EMT resulting mesenchymal cells. We propose that Snail1 and LOXL2
regulate heterochromatin during this process, which may be crucial to allow the genome
reorganization required to complete EMT.Tot i estar enriquida en marques repressores, l’heterocromatina es transcriu activament i dóna lloc a grans quantitats d’ARNs no codificants. Aquests trànscrits són responsables de la formació i el manteniment de l’heterocromatina, però com es regula la seva transcripció segueix sent quelcom poc clarificat. En aquesta tesi demostrem que el factor de transcripció Snail1 reprimeix la transcripció pericentromèrica en cèl·lules de ratolí i regula l’organització de l’heterocromatina a través de l’acció de la LOXL2, que deamina l’H3K4. Snail1 té un paper clau en la transició epiteli-mesènquima (EMT). Aquí demostrem que, també durant aquest procés, Snail1 és responsable de la regulació de la transcripció pericentromèrica. A l’inici de l’EMT, l’HP1α, una de les principals proteïnes estructurals de l’heterocromatina, es desprèn de forma transitòria de l’heterocromatina. Aquest esdeveniment està regulat per Snail1 i LOXL2 i coincideix amb una disminució de la transcripció pericentromèrica. El bloqueig de la baixada dels trànscrits durant l’EMT compromet les capacitats migratòries i invasives de les cèl·lules mesenchimals que en resulten. Així doncs, proposem que Snail1 i LOXL2 regulen l’heterocromatina durant aquest procés, i així permeten que tingui lloc la reorganització genòmica que deu ser necessària per tal que es completi la EMT.
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Götherström, Cecilia. "Characterisation of human fetal mesenchymal stem cells /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-139-3/.
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O'Donoghue, Keelin. "Fetomaternal tracking of fetal mesenchymal stem cells." Thesis, Imperial College London, 2005. http://hdl.handle.net/10044/1/11850.
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Ingman, Karen Ann. "Isolation and characterisation of placental mesenchymal cells." Thesis, University of Manchester, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.492833.
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The origin and functions of placental mesenchymal cells, including the macrophage population known as Hofbauer cells, are poorly understood. It is believed these cells may be involved in morphogenesis of the placental villus during development. Speculation over their origin leads to the possibility they may originate from a stem cell population that persists throughout gestation. If significant quantities of stem cells could be isolated from placenta, this would provide an alternative, easily accessible and ethically acceptable source of cells for applications in medicine.
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Branch, Matthew James. "Mesenchymal stem cells and the ocular surface." Thesis, University of Nottingham, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.665484.
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Interest in Mesenchymal Stem Cells for ophthalmic regenerative medicine is increasing. These cells have an increasing array of abilities that allow them to promote wound healing through a number of different mechanisms. The area of mesenchymal stem cell research is large and complex, with many differing names, criteria, sources and culture techniques. Thorough characterisation is crucial if they are to be developed for therapeutic use. Research into fetal liver mesenchymal stem cells represents a small proportion of what is known about these cells although some evidence points to important differences between those found in the bone marrow of adults. These cells may be able to aid corneal regeneration or provide a suitable model for other mesenchymal stem cells. Detailed characterisation of plastic adherent fetal liver was carried out. These cells successfully met the International Society of Cellular Therapy's minimal criteria for mesenchymal stem cells. Their phenotype and genotype (karyotype and telomere length) were assessed over extended passaging. Marker expression was found to decrease in correlation with telomere shortening and increasing cytogenetic anomalies. Fetal liver mesenchymal stem cell colony forming abi lities were investigated and although colonies proliferated substantially marker profiles in each varied and did not conform to the minimal criteria. Mesenchymal stem cells do not generate an immune response and most are also reported to suppress the cellular immune system. Although fetal liver mesenchymal stem cells did not generate an immune response when incubated with lymphocytes they did not possess the ability to suppress stimulation by third party antigens. Fetal liver mesenchymal stem cell interaction with amniotic membrane, as a potential candidate for a culture substrate and carrier was also analysed. Amniotic membrane allowed attachment and proliferation whilst retaining a mesenchymal stem cell phenotype after 21 days in culture.
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Gullo, Francesca. "Mesenchymal stem cell subsets from human synovium." Thesis, University of Aberdeen, 2012. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=195745.
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Zong, Fang. "Studies on syndecan-1 in mesenchymal tumors." Stockholm : Department of Laboratory Medicine, Karolinska Institutet, 2010. http://diss.kib.ki.se/2010/978-91-7409-749-8/.
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Youngstrom, Daniel W. "Mesenchymal Stem Cell Mechanobiology and Tendon Regeneration." Diss., Virginia Tech, 2015. http://hdl.handle.net/10919/64422.
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Tendon function is essential for quality of life, yet the pathogenesis and healing of tendinopathy remains poorly understood compared to other musculoskeletal disorders. The aim of regenerative medicine is to replace traditional tissue and organ transplantation by harnessing the developmental potential of stem cells to restore structure and function to damaged tissues. The recently discovered interdependency of cell phenotype and biophysical environment has created a paradigm shift in cell biology. This dissertation introduces a dynamic in vitro model for tendon function, dysfunction and development, engineered to characterize the mechanobiological relationships dictating stem cell fate decisions so that they may be therapeutically exploited for tendon healing.
Cells respond to mechanical deformation via a complex set of behaviors involving force-sensitive membrane receptor activity, changes in cytoskeletal contractility and transcriptional regulation. Effective ex vivo model systems are needed to emulate the native environment of a tissue and to translate cell-matrix forces with high fidelity. A naturally-derived decellularized tendon scaffold (DTS) was invented to serve as a biomimetic tissue culture platform, preserving the structure and function of native extracellular matrix. DTS in concert with a newly designed dynamic mechanical strain system comprises a tendon bioreactor that is able to emulate the three-dimensional topography, extracellular matrix proteins, and mechanical strain that cells would experience in vivo. Mesenchymal stem cells seeded on decellularized tendon scaffolds subject to cyclic mechanical deformation developed strain-dependent alterations in phenotype and measurably improved tissue mechanical properties. The relative tenogenic efficacies of adult stem cells derived from bone marrow, adipose and tendon were then compared in this system, revealing characteristics suggesting tendon-derived mesenchymal stem cells are predisposed to differentiate toward tendon better than other cell sources in this model.
The results of the described experiments have demonstrated that adult mesenchymal stem cells are responsive to mechanical stimulation and, while exhibiting heterogeneity based on donor tissue, are broadly capable of tenocytic differentiation and tissue neogenesis in response to specific ultrastructural and biomechanical cues. This knowledge of cellular mechanotransduction has direct clinical implications for how we treat, rehabilitate and engineer tendon after injury.Ph. D.
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Duffy, Cairnan Robert Emmett. "New culture systems for mesenchymal stem cells." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/21044.
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Mesenchymal stem cells are the stem cells that replace the bone, fat and cartilage tissues of the human body. In addition, these cells can form muscles, ligaments and neurons. This wide multipotency has made mesenchymal stem cells of particular interest in the fields of tissue engineering and regenerative medicine. Furthermore, mesenchymal stem cells can modulate the immune system by reducing factors that increase inflammation and immune recognition. This immune recognition suppression has resulted in their application as part of bone marrow transplantation in the prevention of 'graft versus host‘ disease. There are hundreds of on-going clinical trials using these cells for the treatment of autoimmune diseases such as type I diabetes, arthritis and multiple sclerosis. The increasing importance of these cells has brought in to focus the culture methods used to for their expansion and manipulation. Currently, animal derived components are used as surfaces for their growth and as components in the culture media. This exposes these cells to animal pathogens and antigens that can be passed to the recipients of these cells. In the first part of this thesis, polymer microarrays were employed to identify alternatives to the biological surfaces currently used for mesenchymal stem cell culture. This platform allowed hundreds of polyacrylates/acrylamides and polyurethanes to be simultaneously scrutinised to identify surfaces that could support their growth and maintain their stem cell characteristics. Identified polymer surfaces were monitored in long-term culture (10 passages) and were shown to retain the cell phenotype and capacity to differentiate, thus providing chemically defined substrates for long-term mesenchymal stem cell culture. In the second part of this thesis, a 'smart‘ polymer microarray of hydrophilic cross-linked polymers (hydrogels) were used to remove another key biological component of culture, trypsin. These 'smart‘ hydrogels modulated their properties depending on the temperature. Hydrogels that could trigger mesenchymal stem cell release after a reduction in temperature were identified. A unique passaging system using a modest temperature reduction for 1h was developed as a passaging method. Cells were maintained and monitored for 10 passages using this novel enzyme free passaging method. Analysis of the mesenchymal stem cell phenotype and differentiation capacity revealed this method superior than conventional culturing methods. In the final part of this thesis, a 'knowledge-based‘ small molecule library was designed, which could potentially yield small molecules to manipulate/enhance the mesenchymal stem cell state without the use of biological components. The key protein pathways that control the stem cell state were examine with the bioinformatics tool GeneGo was used to identify compounds that affected these pathways, resulting in selection of 200 small molecules. The effect of the small molecules on the mesenchymal phenotype was examined and 5 small molecules were identified that enhanced the phenotype of these cells. The anti-inflammatory properties associated with the hit compounds led to the investigation of their effects on key surface proteins associated with the immune-modulatory state of the cells. In this preliminary study, two of the small molecules, estriol and spermine, increased the expression of a key mesenchymal stem cell marker STRO-1 and down regulated ICAM-1, a critical component of the immune modulation capacity of this cell type.
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San, Khin MiMi. "tRNA Profiling of Mesenchymal Stem Cell Exosome." VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5638.
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Background: Exosomes have great potential in regenerative medicine through the
transfer of their bioactive cargos, such as RNA. tRF RNA and tiRNA are tRNAderived
non-coding RNA. Here, we sought to identify the tRF/tiRNA profile in human
mesenchymal stem cell (hMSC) exosomes. Methods: Bone marrow hMSCs were
cultured with/without osteogenic differentiation medium and exosomes were
harvested. RNA was extracted from: 1) control cells (Cell-NT); 2) control exosomes
(EXO-NT); 3) differentiated cells (Cell-OM); 4) exosomes produced by differentiated
cells (EXO-OM). RNA was sequenced to profile the small RNA with a focus on
tRF/tiRNA. Results: tRF/tiRNA was highly enriched in hMSC exosomes. Less
diversity was seen in the tRF/tiRNA profile in exosomes than that in parent cells.
Selective tRF/tiRNA were packed into MSC exosomes and their profile is dependent
on the cell maturation status. Conclusions: Our results suggest that tRF/tiRNA may
play a role in mediating the function of exosomes in tissue regeneration.
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Stoianovici, Charles. "Directing Mesenchymal Stem Cells for Periodontal Regeneration." VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5335.
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Background: Directing autogenous Mesenchymal Stem Cell (MSC) to defect sites has a great promise in bone regeneration. We designed a MSC specific, bone affinity peptide (E7HA7) by conjugating E7 with a polyglutamate hydroxyapatite (HA) binding motif. We sought to characterize the in-vivo releasing pattern and bioactivity of E7HA7. Methods: HA discs were coated with fluorescent labeled peptides E7HA7, E7HA2 or E7 were subcutaneously implanted in Sprague Dawley rats. In an ectopic bone formation model was used to test the in-vivo bioactivity of E7HA7 conjugated to DBM. Results: E7HA7 showed slower peptide release from scaffolds in comparison to other groups, being statistically significant at week 2 compared to E7, and to E7HA2 at week 4 and 8. In ectopic model, the medians for new bone formation in each group were: iDBM=0.041mm3, iDBM-E7=0.071mm3, aDBM=0.138mm3, and aDBM-E7=0.192mm3. Conclusions: Conjugation of E7 to polyglutamate bone binding domain showed slow releasing kinetics and osteoinductive potential.
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Vaghjiani, Rasilaben Jethalal. "Isolation and characterisation of mesenchymal stem cells." Thesis, Imperial College London, 2008. http://hdl.handle.net/10044/1/4416.
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MSCs have great therapeutic potential and are currently used in various clinical trials. However, the extremely low frequency of MSCs and the absence of a known cell-specific marker have made their purification and identification a highly challenging goal. Our hypothesis is that identification of a MSC specific cell surface marker would facilitate isolation of a pure population of MSCs, which in clinical studies may enhance the subsequent regenerative effect in comparison to a heterogeneous MSC population. Our aim therefore was to attempt to identify such MSC-specific markers using a transcriptomics approach. Individual clones were isolated after seeding bone marrow mononuclear cells from BALB/b and BALB/c mice in 5% oxygen tension. All clones had the ability to differentiate into adipocytes, chondrocytes, and osteoblasts, and to self-renew, and were therefore functionally characterised as MSCs. All murine MSC clones consistently expressed very high levels of Sca-1. Cytogenetic analysis of clones revealed an abnormal karyotype of 69 chromosomes and transplantation of cells into immuno-compromised SCID mice revealed no evidence of tumour formation after 7 months indicating that cells were not malignant. A rigorous genome-wide supervised microarray analysis revealed six genes were differentially expressed on the MSC clones in comparison to various controls - STEAP1, STEAP2, ly6f, versican, vitamin D receptor, and H2-M9. Two-dimensional hierarchical clustering of 28 different arrays revealed both STEAP genes and vitamin D receptor also had a similar expression pattern to Sca-1. Thus STEAP1 and STEAP2 were the only two cell membrane protein encoding genes identified by both analysis methods. Importantly, flow cytometry analysis revealed STEAP2 was differentially expressed in normal diploid multipotent human bone marrow stromal cells (hBMSCs) compared to fibroblasts and freshly isolated bone marrow cells. Furthermore, western blot analysis revealed STEAP1 was significantly expressed in hBMSCs, but not by human fibroblasts or human chondrocytes. STEAP1 depletion by RNA interference resulted in decreased cell adherence to tissue culture plastic. Results suggest STEAP1 and STEAP2 may be novel MSC markers in murine and in human cells. Further work is needed to elucidate their role in MSCs and to establish their usefulness as potential cell-specific markers.
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Liang, Jennifer Kimiko. "Differential requirements of the hindbrain and mesenchyme on inner ear patterning." College Park, Md.: University of Maryland, 2009. http://hdl.handle.net/1903/9114.
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Thesis (M.S.) -- University of Maryland, College Park, 2009.Thesis research directed by: Dept. of Biology. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.
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Nie, Yingjie, and 聶瑛潔. "Defective dendritic cells and mesenchymal stromal cells in systemic lupus erythematosus and the potential of mesenchymal stromal cells ascell-therapy." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B43278681.
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Tan, E.-Jean. "Transcriptional and Epigenetic Regulation of Epithelial-Mesenchymal Transition." Doctoral thesis, Uppsala universitet, Ludwiginstitutet för cancerforskning, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-206120.
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The transforming growth factor beta (TGFβ) is a cytokine that regulates a plethora of cellular processes such as cell proliferation, differentiation, migration and apoptosis. TGFβ signals via serine/threonine kinase receptors and activates the Smads to regulate gene expression. Enigmatically, TGFβ has a dichotomous role as a tumor suppressor and a tumor promoter in cancer. At early stages of tumorigenesis, TGFβ acts as a tumor suppressor by exerting growth inhibitory effects and inducing apoptosis. However, at advanced stages, TGFβ contributes to tumor malignancy by promoting invasion and metastasis. The pro-tumorigenic TGFβ potently triggers an embryonic program known as epithelial-mesenchymal transition (EMT). EMT is a dynamic process whereby polarized epithelial cells adapt a mesenchymal morphology, thereby facilitating migration and invasion. Downregulation of cell-cell adhesion molecules, such as E-cadherin and ZO-1, is an eminent feature of EMT. TGFβ induces EMT by upregulating a non-histone chromatin factor, high mobility group A2 (HMGA2). This thesis focuses on elucidating the molecular mechanisms by which HMGA2 elicits EMT. We found that HMGA2 regulates a network of EMT transcription factors (EMT-TFs), such as members of the Snail, ZEB and Twist families, during TGFβ-induced EMT. HMGA2 can interact with Smad complexes to synergistically induce Snail expression. HMGA2 also directly binds and activates the Twist promoter. We used mouse mammary epithelial cells overexpressing HMGA2, which are mesenchymal in morphology and highly invasive, as a constitutive EMT model. Snail and Twist have complementary roles in HMGA2-mesenchymal cells during EMT, and tight junctions were restored upon silencing of both Snail and Twist in these cells. Finally, we also demonstrate that HMGA2 can epigenetically silence the E-cadherin gene. In summary, HMGA2 modulates multiple reprogramming events to promote EMT and invasion.
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Zachos, Terri A. "Gene-augmented mesenchymal stem cells in bone repair." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1146076285.
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Kühl, Tobias Hans-Jürgen [Verfasser], and Leena [Akademischer Betreuer] Bruckner-Tuderman. "Mesenchymal stromal cell therapy for dystrophic epidermolysis bullosa." Freiburg : Universität, 2016. http://d-nb.info/1119452716/34.
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Palmer, `Simon Buzz Lee. "Tissue engineering osteochondral composites using mesenchymal stem cells." Thesis, University of York, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.533508.
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Cheung, Pak-yan, and 張柏欣. "Esophageal carcinogenesis: immortalization, transformation and epithelial-mesenchymal transition." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B41290379.
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Wu, Haojia, and 吳浩佳. "Role of mesenchymal stem cells in proteinuric nephropathy." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/206678.
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Proteinuria has been recognized as a common feature in many forms of chronic kidney disease (CKD). As traditional medications for proteinuric nephropathy, such as blockade of the renin-angiotensin system (RAS), has only achieved limited clinical success, more effective renoprotective strategies need to be explored. Bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) have recently shown promise as a therapeutic tool in acute kidney injury (AKI) models. The therapeutic potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) in proteinuric nephropathy models is unknown.
Using a co-culture model of human proximal tubular epithelial cells (PTECs) and BM-MSCs, I first examined the potential effect of BM-MSCs in albumin-induced pro-inflammatory response and epithelial-to-mesenchymal transition (EMT) in PTECs. The unstimulated BM-MSCs exerted moderate suppressive effect on tubular inflammation as only albumin-induced CCL-2 and CCL-5 expression was attenuated in PTECs. When concomitantly stimulated by albumin excess, however, BM-MSCs remarkably suppressed albumin-induced tubular IL-6, IL-8, TNF-α, CCL-2, and CCL-5 expression, suggesting albumin overloaded milieu to be a prerequisite for them to fully exhibit their anti-inflammatory effects. This effect was mediated via deactivation of tubular NF-κB signaling as BM-MSCs prevented the overexpression of p-IκB and nuclear translocation of NF-κB. In addition, albumin-induced tubular EMT, as shown by the loss of E-cadherin and induction of α-SMA, FN-1 and collagen IV in PTECs, was also prevented by BM-MSC co-culture.
To dissect the mechanism of action, I next explored the paracrine factors secreted by BM-MSCs under an albumin-overloaded condition and studied their contribution to the protective effect on tubular inflammation and EMT. Albumin-overloaded BM-MSCs per se overexpressed 34 paracrine factors, of which hepatocyte growth factor (HGF) and TNFα-stimulating gene (TSG)-6 were regulated by P38 and NF-κB signaling. These paracrine factors suppressed both the proinflammatory and profibrotic phenotypes in albumin-induced PTECs. Neutralizing HGF and TSG-6 abolished the anti-inflammatory and anti-EMT effects of BM-MSC co-culture in albumin-induced PTECs, respectively.
Finally, in albumin-overloaded mice, a well established murine model reminiscent of human CKD, treatment with mouse BM-MSCs markedly reduced BUN, tubular CCL-2 and CCL-5 expression, interstitial macrophage, α-SMA and collagen IV accumulation independent of changes in proteinuria, together with upregulated renal cortical expression of HGF. Exogenous BM-MSCs were detected in their kidneys by PKH-26 staining. Collectively, these in vitro and in vivo data suggest a modulatory effect of BM-MSCs on albumin-induced tubular inflammation and fibrosis and underscore a therapeutic potential of BM-MSCs for CKD in the future.published_or_final_version
Medicine
Doctoral
Doctor of Philosophy