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Cell Journal، جلد ۱۵، شماره Suppl ۱، صفحات ۶-۶
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عنوان انگلیسی Is-12: Differentiation, Dedifferentiation and Transdifferentiation Potential and Mechanisms of Human Bone Marrow-Derived Mesenchymal Stem Cells
چکیده انگلیسی مقاله Objective: Mesenchymal stem cells (MSC) have a multilineage differentiation potential. Some years ago it was common opinion that during differentiation MSC become lineage restricted and unipotent in an irreversible manner. However, current data imply that even terminally differentiated cells transdifferentiate across lineage boundaries, and thus serve as progenitors for other lineages. This raises the questions of whether transdifferentiation occurs via dedifferentiation to a progenitor cell and subsequent differentiation or via direct cell-to-cell conversion, and whether the potency of MSC decreases or increases during differentiation. In this lecture, we will present the state of the art and own results on human MSC differentiation, de- and transdifferentiation in context of regenerative medicine. The focus lies on adipogenesis and subsequent de-/transdifferentiation. Methods and Materials: Human MSC were isolated from bone marrow aspirates and expanded up to passage 4. Then, they were differentiated into the adipogenic (15 days), osteogenic (28 days) and chondrogenic lineage (28 days). Differentiated cells were isolated from their matrix and then dedifferentiated for 2-4 weeks in MSC expansion medium. Subsequently, dedifferentiated cells of all 3 lineages were again differentiated into 3 lineages. To analyze transdifferentiation via direct cell-tocell conversion, in a further approach, differentiated cells were cultivated in differentiation medium of the other lineages. In both approaches, also single cell analysis was performed. In general, cultures were studied using histology, immunohistochemical staining, FACS, qPCR and GeneChips. Bioinformatics was performed to identify molecular key-players. Results: GeneChip analysis in combination with Bioinformatics revealed a deep insight into adipogenic, osteogenic and chondrogenic differentiation and dedifferentiation. As shown here for adipogenic differentiation and dedifferentiation, we detected distinct genes whose upregulation (DHCR24, G0S2, MAP2K6, SESN3) and downregulation (DST, KAT2, MLL5, RB1, SMAD3, ZAK) is associated with cell cycle arrest in differentiated cells and perhaps narrow down the lineage potency. Upregulation of CCND1, CHEK, HGF, HMGA2 and downregulation of CCPG1, RASSF4, RGS2 is associated with cell cycle progression and maybe motivates dedifferentiation of differentiated cells. Interestingly, and of potential high importance for cell-based regenerative medicine, we found that the dedifferentiated cells of all three lineages have a multilineage potency comparable to MSC, and also observed an associative role of proliferation genes with cell cycle arrest and progression. Direct cultivation of adipogenic differentiated MSC in osteogenic medium resulted in a mixture of both cell types, as shown by staining of lipid droplets and of mineralized bone matrix, and qPCR of adipogenic (PPARG, FABP4) and osteogenic (SPP1, RUNX2) marker genes. Mix cultures were also observed in chondrogenic medium (PPARG, FABP4, SOX9, COL2A1 positive). Conclusion: Our results indicate that transdifferentiation of differentiated MSC proceeds via dedifferentiation and correlates with cell cycle arresting and driving genes. Understanding of de-/transdifferentiation mechanisms may allow the use of cells from easily available cell sources in regenerative medicine. Our results will be presented in this keynote in context of the international state of the art.
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نشانی اینترنتی http://celljournal.org/journal/article/abstract/777
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