Characterization of hematopoietic stem cell–derived microglia-like cells in nonhuman primates

Abstract Hematopoietic stem cell transplantation (HSCT) is the current standard of care for several neurotrophic lysosomal storage disorders. The therapeutic mechanism of HSCT is believed to be mediated by the engraftment of hematopoietic stem cell progeny into the brain as microglia-like cells (MLCs). However, the engraftment of MLCs and their transcriptomic identity relative to endogenous microglia remain poorly understood. In this study, we used an autologous nonhuman primate (NHP) HSCT model to investigate the engraftment of MLCs after gene-modified autologous HSCT. We observed engraftment of gene-marked MLCs across a cohort of 5 NHPs. MLCs engrafted throughout diverse brain regions, adopted a homeostatic ramified morphology, and upregulated core microglial transcripts. We then used single-cell RNA sequencing to more rigorously evaluate the transcriptome of MLCs, revealing a border-associated macrophage-like phenotype. Our findings offer critical insights into the engraftment and behavior of MLCs after HSCT, laying the groundwork for their future use as a directed therapeutic option.