A Mac2-positive progenitor-like microglial population survives independent of CSF1R signaling in adult mouse brain

Microglia are the resident myeloid cells in the central nervous system (CNS). The majority of microglial population relies on Csf1r signaling for survival and maintenance. However, a small subset of microglia in the murine brain can survive without Csf1r signaling, and reestablishes homeostasis after Csf1r signaling returns. Using single-cell RNA-seq, we characterized the heterogeneous microglial populations under Csf1r inhibition, including microglia lacking homeostatic markers and populations with elevated markers of monocytes, granulocytes and dendritic cells. Importantly, Mac2 is distinctively expressed in a subset of Csf1r-independent microglia cells, which were highly proliferative and shared striking similarities with those of microglial progenitors in yolk sac and early embryos. Lineage-tracing revealed that the Mac2+ population is of microglial origin and does not come from periphery monocytes. In non-treated mouse brains, Mac2+ microglia exhibited progenitor transcriptomic signature indistinguishable from those survived csf1r inhibition, supporting Mac2+ progenitor-like cells are present among homeostatic microglia.