Ricardo Vieira

PhD, Novo Nordisk Scientist

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

Abstract: Glial dysfunction is a causal contributor to a broad variety of neurological conditions. In such conditions, the replacement of diseased glia by healthy human glial progenitor cells (hGPCs) might provide real therapeutic benefit, given their ability to disperse and colonize their hosts while giving rise to new astrocytes and oligodendrocytes. Yet, while hGPCs can outcompete and replace their mouse counterparts in a variety of experimental therapeutic models, it has remained unclear if allografted hGPCs can replace other human cells, diseased or otherwise. 

To assess whether implanted healthy human glia can replace their diseased counterparts in vivo, we engrafted WT hGPCs produced from human embryonic stem cells into the striata of adult mice that had been neonatally chimerized with mutant Huntingtin-expressing hGPCs. The WT hGPCs outcompeted and ultimately eliminated their Huntington’s disease (HD) counterparts, repopulating the host striata with healthy glia. Single-cell RNA sequencing revealed that WT hGPCs acquired a 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. These data suggest that aged and diseased human glia may be broadly replaced in adult brain via the implantation of younger healthy hGPCs.