Basic biology of reprogramming IPSC There has been great interest in the production of pluripotent iPSCs from adults, because of their biologic interest and potential value for studying mechanisms of human disease, and potentially ultimately for regenerative medicine. However, the induction requires several weeks and is generally very inefficient, in that only a small fraction of the cells are induced. On prolonged cultivation with inducing factors, almost all cells can give rise to progeny among which are iPSCs, so that conversion appears to involve some stochastic event that can occur in many cells rather than being limited to a few pre-determined cells in any culture. However, cell populations may be heterogeneous with respect to their ease of conversion. Conversion of somatic cells to IPSCs may follow a defined sequence of events, possibly involving early repression of differentiation markers and morphologic changes reminiscent of a transition from mesenchymal to epithelial cells, followed by the expression of ES-like markers of dedifferentiation, and finally by the activation of endogenous Nanog. Also, not all emerging colonies develop into fully pluripotent cells, suggesting that the conversion process requires multiple separable steps. Even after development of iPSCs they may retain markers such as sites of DNA methlylation that retain traces of their cell of origin, and progressive passage of the cells may cause them to be progressively more like embryonic stem (ES) cells, Epigenetic reprogramming of iPS cells: When induced to pluripotency, somatic cells acquire the features of ES cell-like states in their gene expression and epigenetic status. Human ES cells have histone modification states that allow them to differentiate into all three germ layers when instructed. So-called bivalent H3K4methylation and H3K27methylation on developmentally important genes are conserved in pluripotent cells. In addition, IPSCs acquire an ES cell-like global DNA methylation pattern. However, current factor-based reprogramming does not completely reprogram somatic epigenetic state to the ES cell state, and cells retain s significant number of iPSC specific differential methylated regions (DMRs) distinct from those of human ES cells. The aberrant epigenetic reprogramming affects the differentiation potential of IPSCs. Due to the extremely low efficiency of human somatic cell reprogramming. the elucidation of epigenetic changes during reprogramming induction has been challenging. By combining the technical advancement in analyzing global gene expression. DNA methylation analysis, and histone modification with isolation of cells of intermediate stages of reprogramming. we will reveal the sequence of epigenetic changes. Considering the importance of application of iPSCs in cell therapy and novel in vitro disease modeling, dissecting the epigenetic modification of reprogramming has high impact.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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