Donor cell memory confers a metastable state of directly converted cells

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Kee Pyo Kim
  • Cui Li
  • Daria Bunina
  • Hyun Woo Jeong
  • Julia Ghelman
  • Juyong Yoon
  • Borami Shin
  • Hongryeol Park
  • Dong Wook Han
  • Judith B. Zaugg
  • Johnny Kim
  • Tanja Kuhlmann
  • Ralf H. Adams
  • Kyung Min Noh
  • Goldman, Steven Alan
  • Hans R. Schöler
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.
OriginalsprogEngelsk
TidsskriftCell Stem Cell
Vol/bind28
Udgave nummer7
Sider (fra-til)1291-1306.e10
Antal sider17
ISSN1934-5909
DOI
StatusUdgivet - 2021

Bibliografisk note

Funding Information:
We thank Gunnar Hargus, Anna Preisner, and Karin Hagemeier for sharing materials. We also thank Martin Stehling and Dagmar Zeuschner for flow cytometry and electron microscopy. We also thank Jeanine Müller-Keuker for creating the graphical abstract. This work was supported by the Max Planck Society (Germany) . Work in the Goldman lab was supported by NIMH (United States) , NINDS (United States) , the PML Consortium (United States) , the Adelson Medical Research Foundation (United States) , the Novo Nordisk Foundation (Denmark) , and the Lundbeck Foundation (Denmark) . Work in the Noh lab was supported by the DFG (Germany, SPP 1738 to K.M.N.) and the EIPOD postdoctoral fund from EMBL (Germany, to D.B.). R.H.A. and H.P. were supported by the DFG (Germany, project 391580220 ).

Publisher Copyright:
© 2021 Elsevier Inc.

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