Development of a chimeric model to study and manipulate human microglia in vivo (scRNA-seq dataset)

iPSC-derived microglia offer a powerful tool to study microglial homeostasis and disease-associated inflammatory responses. Yet, microglia are highly sensitive to their environment, exhibiting transcriptomic deficiencies when kept in isolation from the brain. Furthermore, species-specific genetic variations demonstrate that rodent microglia fail to fully recapitulate the human condition. To address this, we developed an approach to study human microglia within a surrogate brain environment. Transplantation of iPSC-derived hematopoietic-progenitors into the postnatal brain of humanized, immune-deficient mice results in context-dependent differentiation into microglia and other CNS macrophages, acquisition of an ex vivo human microglial gene signature, and responsiveness to both acute and chronic insults. Most notably, transplanted microglia exhibit robust transcriptional responses to Ab-plaques that only partially overlap with that of murine microglia, revealing new, human-specific Ab-responsive genes. We therefore have demonstrated that this chimeric model provides a powerful new system to examine the in vivo function of patient-derived and genetically-modified microglia. iHPCs were transplanted at P1 into male and female MITRG and 5X-MITRG mice then aged for up to 12 months. Whole brains were enzymatically digested and xMGs were isolated via negative MAC sorting from Male MITRG (n=1, 10.5mos), Female MITRG (n=1, 10.5 mos), Male 5X-MITRG (n=2, 11.5 and 12 mos.), and Female 5X-MITRG (n=2, 10.5 mos.). Single-cell RNA sequencing was then performed utilizing the 10X genomics platform..