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간세포성장인자 발현 중간엽줄기세포의 간섬유화 치료
- Alternative Title
- Myung-Deok Kim
- Author(s)
- 김명덕
- Alternative Author(s)
- Myung-Deok Kim
- Advisor
- 이재호
- Department
- 일반대학원 분자과학기술학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2009-02
- Language
- eng
- Alternative Abstract
- Purpose: Bone marrow-derived stem cells (BMSC) have been reported to be beneficial for the treatment of liver fibrosis in several studies. However, improvement in its efficacy is needed for this cell therapy to be considered as a practical therapy against liver fibrosis. Here, we investigated whether cell therapy using genetically engineered mesenchymal stem cells (MSC) to overexpress hepatocyte growth factor (HGF) resulted in a better therapeutic effect than MSC alone. The underlying mechanisms for the therapeutic effect and the bio-distribution of transplanted cells were also investigated. Materials & Methods: Liver fibrosis was induced by the intraperitoneal injection of dimethylnitrosamine. Adenovirus with HGF cDNA was infected to MSC to make HGF-overexpressing MSC (MSC/HGF). Normal or fibrotic rats were intra-splenically injected with the cells, and sacrificed 12 days after. Cell tracking was performed by using MSC radio-labelled with 111Indium. Results: Evidently, tissue fibrosis measured histochemically was reduced after MSC delivery, and even more by MSC/HGF, corroborating with elevated HGF levels in portal vein. Importantly, collagen levels from liver extract measured by Sirius red dye revealed the actual decrease after MSC/HGF delivery, suggesting the recovery of the fibrosis. HGF mRNA transcripts in liver and HGF protein in portal vein were significantly elevated by delivery of MSC/HGF. Furthermore, serum parameters showing the liver function were improved in MSC/HGF group, suggesting that transplantation with MSC/HGF resulted in not only the reduction of liver fibrosis but also the improvement of hepatocyte function. As for the underlying mechanisms, mRNA levels of the fibrogenic cytokines, PDGF-bb and TGF-β1, were significantly decreased after MSC/HGF delivery. Subsequent to the decrease of collagen, expressions of MMP-9, MMP-13, MT1-MMP and uPA were augmented by MSC/HGF, whereas TIMP-1 expression was reduced. It was of note that, even without immunosuppressant, a considerable amount of xeno-transplanted cells could survive for 12 days in both MSC and MSC/HGF groups. Both cells were found mainly in the spleen and the liver and additionally, in the lung of fibrosis group from 0 day and 2 day. Notably, xeno-transplanted cells were stably maintained only in fibrotic group. Conclusion: Cell therapy with MSC/HGF resulted in a better therapeutic effect than MSC alone probably through various anti-fibrotic activities of HGF and relatively stable maintenance of MSC. Thus, MSC/HGF would be a promising candidate as a cell therapy against liver fibrosis.
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Molecular Science and Technology > 3. Theses(Master)
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