Young glial progenitor cells competitively replace aged and diseased human glia in the adult chimeric mouse brain
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Young glial progenitor cells competitively replace aged and diseased human glia in the adult chimeric mouse brain. / Vieira, Ricardo; Mariani, John N.; Huynh, Nguyen P.T.; Stephensen, Hans J.T.; Solly, Renee; Tate, Ashley; Schanz, Steven; Cotrupi, Natasha; Mousaei, Marzieh; Sporring, Jon; Benraiss, Abdellatif; Goldman, Steven A.
In: Nature Biotechnology, 2024.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Young glial progenitor cells competitively replace aged and diseased human glia in the adult chimeric mouse brain
AU - Vieira, Ricardo
AU - Mariani, John N.
AU - Huynh, Nguyen P.T.
AU - Stephensen, Hans J.T.
AU - Solly, Renee
AU - Tate, Ashley
AU - Schanz, Steven
AU - Cotrupi, Natasha
AU - Mousaei, Marzieh
AU - Sporring, Jon
AU - Benraiss, Abdellatif
AU - Goldman, Steven A.
N1 - Publisher Copyright: © 2023, The Author(s).
PY - 2024
Y1 - 2024
N2 - Competition among adult brain cells has not been extensively researched. To investigate whether healthy glia can outcompete diseased human glia in the adult forebrain, we engrafted wild-type (WT) human glial progenitor cells (hGPCs) produced from human embryonic stem cells into the striata of adult mice that had been neonatally chimerized with mutant Huntingtin (mHTT)-expressing hGPCs. The WT hGPCs outcompeted and ultimately eliminated their human Huntington’s disease (HD) counterparts, repopulating the host striata with healthy glia. Single-cell RNA sequencing revealed that WT hGPCs acquired a YAP1/MYC/E2F-defined dominant competitor phenotype upon interaction with the host HD glia. WT hGPCs also outcompeted older resident isogenic WT cells that had been transplanted neonatally, suggesting that competitive success depended primarily on the relative ages of competing populations, rather than on the presence of mHTT. These data indicate that aged and diseased human glia may be broadly replaced in adult brain by younger healthy hGPCs, suggesting a therapeutic strategy for the replacement of aged and diseased human glia.
AB - Competition among adult brain cells has not been extensively researched. To investigate whether healthy glia can outcompete diseased human glia in the adult forebrain, we engrafted wild-type (WT) human glial progenitor cells (hGPCs) produced from human embryonic stem cells into the striata of adult mice that had been neonatally chimerized with mutant Huntingtin (mHTT)-expressing hGPCs. The WT hGPCs outcompeted and ultimately eliminated their human Huntington’s disease (HD) counterparts, repopulating the host striata with healthy glia. Single-cell RNA sequencing revealed that WT hGPCs acquired a YAP1/MYC/E2F-defined dominant competitor phenotype upon interaction with the host HD glia. WT hGPCs also outcompeted older resident isogenic WT cells that had been transplanted neonatally, suggesting that competitive success depended primarily on the relative ages of competing populations, rather than on the presence of mHTT. These data indicate that aged and diseased human glia may be broadly replaced in adult brain by younger healthy hGPCs, suggesting a therapeutic strategy for the replacement of aged and diseased human glia.
UR - http://www.scopus.com/inward/record.url?scp=85164959824&partnerID=8YFLogxK
U2 - 10.1038/s41587-023-01798-5
DO - 10.1038/s41587-023-01798-5
M3 - Journal article
C2 - 37460676
AN - SCOPUS:85164959824
JO - Nature Biotechnology
JF - Nature Biotechnology
SN - 1087-0156
ER -
ID: 360256763