Mesenchymal stem cell transplantation mediates tissue repair and regeneration through jak/stat3 activation of host derived tissue trophic factors
Shabbir, Arsalan Qazi
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Stem cell therapy has developed into a promising medicine for a myriad of diseases, including muscular dystrophy and heart disease. Emerging data suggests that the paracrine or trophic actions exerted by stem cells through the release of soluble factors might be important mechanisms for tissue repair and functional improvement after injection of stem cells. Work in this thesis focused on mesenchymal stem cells' (MSCs) potent trophic and immuno-modulatory actions and mechanisms involved for such effects. In chapter two, the immuno-modulatory property of MSCs was examined for the treatment of δ-sarcoglycan-deficient dystrophic hamster muscle without any immunosuppression as MSCs have been postulated to possess immuno-modulatory and trophic capabilities. Indeed, we found circulating levels of inflammatory cells and markers were not elevated after MSC administration. The injected MSCs were found to be trapped in the musculature and found to contribute to both pre-existing and new muscle fibers, and mediate capillary formation. Treated muscles exhibited increased cell cycle activity and attenuated oxidative stress. In chapter three, the trophic actions of MSCs were further examined in the δ-sarcoglycan-deficient dystrophic hamster, which develop dilated cardiomyopathy and heart failure. To accomplish this, we used a non-invasive therapeutic regimen by delivering MSCs (and MSC conditioned medium) into the skeletal muscle bed of the δ-sarcoglycan-deficient hamster. Intramuscularly injected MSCs and MSC-conditioned medium both significantly improved ventricular function one month after MSC administration. Examination of the myocardium found considerable attenuation of apoptosis and fibrosis. Moreover, we found significant myocardial regeneration as demonstrated by the increased nuclear and capillary density, increased expression of cell cycle markers (Ki67 and phosphohistone H3), and expansion of the myocardial c-kit + stem cell pool. Further examination of the trophic effects of MSCs found elevated expression of hepatocyte growth factor (HGF), insulin-like growth factor-2 (IGF-2), and vascular endothelial growth factor (VEGF) in the myocardium. In addition, there was an associated increase in the circulating levels of growth factors, including HGF and associated with mobilization of progenitor stem cells. The work in chapter 3 highlighted a tissue repair mechanism mediated by trophic effects of MSC on host tissues, including the bone marrow and heart. The work performed in chapter 4 focused on the mechanistic aspects of MSC action. We found that the trophic actions of MSCs on host tissues were mediated by STAT3. Consistent with observations in Chapter 2 and 3, MSCs were found to activate STAT3 in vitro and in vivo and up-regulate STAT3 target genes, including growth factors such as HGF and VEGF and other genes involved in cell cycle progression. Moreover, activation of STAT3 was found to be mediated by the GP130 family of cytokines, ligands that were found to be abundantly expressed by MSCs. Finally, while MSC treatment markedly improved cardiac function, activated STAT3 and mobilized stem cells in young hamsters, these beneficial effects were absent in older hamsters. Collectively, the work performed in this thesis provides strong evidence supporting the trophic action of mesenchymal stem cells and that the effects of MSCs on tissue repair are mediated principally through the activation of STAT3 in host tissues.