Young human glial progenitor cells outcompete and replace older and diseased human cells when transplanted into adult human glial chimeric mice

Human glial progenitor cells (hGPCs) are highly migratory, and glial replacement has the potential to treat those neurological disorders in which astrocytic and oligodendrocytic pathology are contributory. Yet it remains unknown whether allografted human glia can out compete diseased cells to achieve therapeutic replacement in the adult human brain.To that end, we engrafted healthy wild-type (WT) hGPCs into the striata of adult mice that had been earlier chimerized neonatally with mutant HTT-expressing hGPCs generated from Huntington disease (HD)-derived human embryonic stemcells. The WT hGPCs effectively out competed and ultimately eliminated their HD counterparts, repopulating the host striata with healthy humanglia. Single-cell transcriptomics revealed that WT hGPCs actively assumed a dominant competitor phenotype upon interaction with their resident HD counter parts.The outcomes of clonal competition depended primarily upon the age difference between competing clones, in that adult-transplanted WT GPCs effectively out competed their isogenic WT counter parts that had been transplanted neonatally, and which were thus necessarily older.These data suggest that both aged and diseased human glia may be broadly replaced in the adult brain by younger and healthier human glial progenitor cells. For HD rescue experiments, striata of Rag1 null mice were transplanted neonatally with HD (G20) hESC-derived EGFP tagged hGPCs neonatally, WT (G19) hESC-derived mCherry tagged hGPCs in adulthood (36 weeks), or co-engrafted with both. WT rescue experiments consisted of neonatal grafts of EGFP tagged G19 hGPCs, adult transplants of mCherry tagged G19 hGPCs, or co-engraftment of both. Animals were sacrificed at ~72 weeks, striata dissociated, and single cells isolated via FACS for mCherry, EGFP, or double negative (mouse) cells for scRNA-seq (10X genomics, v3.1 chemistry).