Donor cell memory confers a metastable state of directly converted cells
Copyright © 2021 Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:28 |
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| Enthalten in: |
Cell stem cell - 28(2021), 7 vom: 01. Juli, Seite 1291-1306.e10 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kim, Kee-Pyo [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 04.08.2021 Date Revised 23.12.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.stem.2021.02.023 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Copyright © 2021 Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
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| 700 | 1 | |a Ghelman, Julia |e verfasserin |4 aut | |
| 700 | 1 | |a Yoon, Juyong |e verfasserin |4 aut | |
| 700 | 1 | |a Shin, Borami |e verfasserin |4 aut | |
| 700 | 1 | |a Park, Hongryeol |e verfasserin |4 aut | |
| 700 | 1 | |a Han, Dong Wook |e verfasserin |4 aut | |
| 700 | 1 | |a Zaugg, Judith B |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Johnny |e verfasserin |4 aut | |
| 700 | 1 | |a Kuhlmann, Tanja |e verfasserin |4 aut | |
| 700 | 1 | |a Adams, Ralf H |e verfasserin |4 aut | |
| 700 | 1 | |a Noh, Kyung-Min |e verfasserin |4 aut | |
| 700 | 1 | |a Goldman, Steven A |e verfasserin |4 aut | |
| 700 | 1 | |a Schöler, Hans R |e verfasserin |4 aut | |
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