Young Glial Progenitor Cells Outcompete Diseased Glial Cells in the Brain

Researchers here report on a demonstration of glial cell competition in the brain, conducted in mice but using human cells. The humanized mice started out with diseased glial cells possessing the mutation characteristic of Huntington's disease. Young human glial progenitor cells without the mutation were transplanted, and subsequently outcompeted the mutated cells, replacing them in the brain. This suggests that a similar strategy could work for a range of neurodegenerative conditions, one treatment to gradually replace problematic supporting cells in the brain. The regenerative medicine community is still struggling to achieve the reliable engraftment and survival of transplanted cells, as well as cost-effective means of generating patient-matched or universal cells, but the road ahead clearly leads to interesting destinations.

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.