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Donor cell memory confers a metastable state of directly converted cells

Item Type:Article
Title:Donor cell memory confers a metastable state of directly converted cells
Creators Name:Kim, K.P. and Li, C. and Bunina, D. and Jeong, H.W. and Ghelman, J. and Yoon, J. and Shin, B. and Park, H. and Han, D.W. and Zaugg, J.B. and Kim, J. and Kuhlmann, T. and Adams, R.H. and Noh, K.M. and Goldman, S.A. and Schöler, H.R.
Abstract:Generation of induced oligodendrocyte progenitor cells (iOPCs) from somatic fibroblasts is a strategy for cell-based therapy of myelin diseases. However, iOPC generation is inefficient, and the resulting iOPCs exhibit limited expansion and differentiation competence. Here we overcome these limitations by transducing an optimized transcription factor combination into a permissive donor phenotype, the pericyte. Pericyte-derived iOPCs (PC-iOPCs) are stably expandable and functionally myelinogenic with high differentiation competence. Unexpectedly, however, we found that PC-iOPCs are metastable so that they can produce myelination-competent oligodendrocytes or revert to their original identity in a context-dependent fashion. Phenotypic reversion of PC-iOPCs is tightly linked to memory of their original transcriptome and epigenome. Phenotypic reversion can be disconnected from this donor cell memory effect, and in vivo myelination can eventually be achieved by transplantation of O4(+) pre-oligodendrocytes. Our data show that donor cell source and memory can contribute to the fate and stability of directly converted cells.
Keywords:Oligodendrocytes, Oligodendrocyte Progenitor Cells, iOPCs, Pericytes, Reprogramming, Direct Conversion, Donor Cell Memory, OLIG2, SOX10, Metastable
Source:Cell Stem Cell
Publisher:Cell Press
Page Range:1291-1306
Date:1 July 2021
Official Publication:https://doi.org/10.1016/j.stem.2021.02.023
PubMed:View item in PubMed

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