Donor cell memory confers a metastable state of directly converted cells
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Donor cell memory confers a metastable state of directly converted cells. / Kim, Kee Pyo; Li, Cui; Bunina, Daria; Jeong, Hyun Woo; Ghelman, Julia; Yoon, Juyong; Shin, Borami; Park, Hongryeol; Han, Dong Wook; Zaugg, Judith B.; Kim, Johnny; Kuhlmann, Tanja; Adams, Ralf H.; Noh, Kyung Min; Goldman, Steven A.; Schöler, Hans R.
In: Cell Stem Cell, Vol. 28, No. 7, 2021, p. 1291-1306.e10.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Donor cell memory confers a metastable state of directly converted cells
AU - Kim, Kee Pyo
AU - Li, Cui
AU - Bunina, Daria
AU - Jeong, Hyun Woo
AU - Ghelman, Julia
AU - Yoon, Juyong
AU - Shin, Borami
AU - Park, Hongryeol
AU - Han, Dong Wook
AU - Zaugg, Judith B.
AU - Kim, Johnny
AU - Kuhlmann, Tanja
AU - Adams, Ralf H.
AU - Noh, Kyung Min
AU - Goldman, Steven A.
AU - Schöler, Hans R.
N1 - Publisher Copyright: © 2021 Elsevier Inc.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - direct conversion
KW - donor cell memory
KW - iOPCs
KW - metastable
KW - OLIG2
KW - oligodendrocyte progenitor cells
KW - oligodendrocytes
KW - pericytes
KW - reprogramming
KW - SOX10
U2 - 10.1016/j.stem.2021.02.023
DO - 10.1016/j.stem.2021.02.023
M3 - Journal article
C2 - 33848472
AN - SCOPUS:85105020422
VL - 28
SP - 1291-1306.e10
JO - Cell Stem Cell
JF - Cell Stem Cell
SN - 1934-5909
IS - 7
ER -
ID: 371930933