Young glial progenitor cells competitively replace aged and diseased human glia in the adult chimeric mouse brain

Ricardo Vieira, John N. Mariani, Nguyen P.T. Huynh, Hans J.T. Stephensen, Renee Solly, Ashley Tate, Steven Schanz, Natasha Cotrupi, Marzieh Mousaei, Jon Sporring, Abdellatif Benraiss, Steven A. Goldman*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

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.

Original languageEnglish
JournalNature Biotechnology
Volume42
Pages (from-to)719-730
Number of pages12
ISSN1087-0156
DOIs
Publication statusPublished - 2024

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