| Mesenchymal stem cells (MSCs), known as multipotent, low-immunogenic cells with easy accessibility from multiple tissues, appear to be an ideal type cells for allo-transplantation. In this study, we worked on MSCs regenerated and alleviated tissue damage in radiated lungs, which may suggest a therapeutic benefit may be obtained with this technique not only in acute phase, but also in chronic stage.The thorax of C57BL/6 mice was exposed to 1400 cGy, and then MSCs from eGFP C57BL/6 or Rosa mice were systemically injected into C57BL/6 mice at 4 hours post thoracic exposure. MSCs limited the injurious effects might by replacing type II alveolar epithelial cells, and their differentiation into typeⅡepithelial cells may partially restore the stem cell pool. MSCs transplanted into the mouse inner ear after drug-induced hair cells injury can also survive, migrate and differentiate towards hair cell-like cells, but did't show significant therapeutic effect. The first part of data indicated that the underling mechanism of stem cells therapy is still under debate, and the effect could only be seen while cells are injected at the time of acute inflammation.The next study was aimed to analyze the engraftment and differentiation behavior of the MSC transplanted at different time points after lung irradiation, and the possible mechanisms were discussed. MSCs from eGFP C57BL/6 mice were systemically injected into the radiated C57BL/6 mice C57BL/6 mice at 4 hours,60 days and 120 days post thoracic exposure respectively. Be contra with Cells injected immediately after injury, cells injected 2 months later were mostly located in the interstitial area, appeared as MFB (myofibrocyte), and showed no effect in fibrosis-ameliorating. Correspondingly, engrafted MSC given just after CTX injury or repeated-infused in youth mdx mice, but not at later times were shown to home to injured muscle, participate in myofibers repair and could partially reconstitute the sarcolemmal expression of dystrophin and ameliorate the level of related specific pathological markers. The second part of data indicated that time window is a key factor in the treatment of injury by MSC transplantation.To further investigate the role of MSCs in lung injury models, the immunologic mechanism of the cell therapy was analysised。Our data indicate that MSC administration immediately after irradiation exposure protects lung tissue from injury by significantly reducing the extent of inflammation. Recently, researchers found the main Th2 cytokines (IL-4 and IL-13) enhance collagen deposition by various mechanisms; and the T helper 1 (Th1) cytokine, such as interferon-y (IFN-γ), might indirectly inhibit fibrosis by reducing pro-fibrotic cytokine expression by Th2 cells. Here we found that MSC seemed to promote the expression of Th2 cytokines, but inhibited both Th1 and Th2 reaction in a short time after injection. On another model, human adipose-derived MSCs were transplanted into ischemia-reperfusion (I/R) kidneys in mouse model. Results showed that MSCs were able to contributed to maintenance of structural integrity and proceeding to subsequent tissue repair process where MSCs as supportive cells promote repair via secreting cytokines. The 3rd part of data indicated that MSC could ameliorate injury not only by differentiate into tissue cells but also by other regulation mechanism, such as immunologic inhibition or innate repair cascade activation.TGF-(31 has been identified as the most important cytokine in the development of fibrosis, and proved to play a significant role in irradiation injured lung model. We investigated its level at three different time points after injury and found it reach a marked high level during rapid onset of fibrosis, whose dramatic change may cause the injected MSCs at the middle and late stages to participate in the fibrosis. In order to observe the underlying effect of TGF-β1, MSCs were cultured in epithelium induction media in vitro, together with TGF-β1, damaged primary lung cells, supernatants of radiation injured lung cells, or plus TGF-β1 antibodies. Epithelial differentiation of MSC was evidently inhibited by medium with 10ng/ml or 100ng/ml TGF-β1 and supernatant or cells of injured lung, whereas regained when added TGF-β1 antibody or using TGF-βreceptor RNAi-MSCs. And cells injected 2 months after radiation plus 6-day TGF-β1 antibody injection partly ameliorated the injury. The last part of the work demonstrated that MSCs engraftment's effect relied on transplantantion plus TGF-(31 controlling, which might be a promising therapy.
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