Charting the transition from in vitro gliogenesis to the in vivo maturation of human glial progenitor cells transplanted into the hypomyelinated mouse brain.

Abstract

Neither rodent models nor in vitro studies of human cells adequately describe the molecular ontogeny of human glial progenitor cells (hGPCs). Here, we use scRNA-seq together with scATAC-Seq and CUT&TAG assessment of chromatin accessibility to track the in vitro genesis and in vivo differentiation of hGPCs from pluripotent stem cells (PSCs). In vitro, the hGPC pool comprises 4 transcriptionally distinct subpopulations, each associated with a distinct pattern of chromatin accessibility and histone modification of stage-dependent genes. After the neonatal transplant of these cells into myelin-deficient shiverer mice (MBP^shi/shi), they differentiate further as astrocytes and oligodendrocytes. A combination of gene co-expression, motif enrichment, cell-trajectory, cell-cell interaction, and spatial transcriptomic analyses reveals that the host environment potentiates the context-dependent differentiation of the hGPCs, via their activation of distinct gene regulatory networks. Together, these data describe the process and pathways by which human PSC-derived GPCs are generated in vitro and diversify in vivo to mature as astrocytes and oligodendrocytes.