Brain microglia are maintained and regenerated from a specialized cellular subset

Microglia, macrophages of the brain parenchyma, are essential for normal brain development and function as well as local immune responses. However, they can also induce and perpetuate severe brain pathology in certain conditions. Microglia are derived from early, fetal yolk sac (YS) progenitors and they are then maintained locally behind the blood brain barrier (BBB) without any external cellular input. It is thought that all microglia cells, like many other tissue-resident macrophages, have self-renewal capacity to maintain its cellularity. Here we, however, report an identification of a minor microglial stem cell-like cells (MgSCs) that are responsible of microglia expansion and maintenance during development and during steady state. MgSCs resemble somatic, unipotent stem cells: they are self-renewing and able to differentiate to the bulk of sessile microglia which , on the need , can dedifferentiate back to MgSCs. Due to their central role in microglia turnover MgSCs can become valuable, therapeutic targets in neuropathological conditions. MgSCs (CD45intCD11bhiF4/80hiLy6chi), bulk microglia cells (CD45intCD11bhiF4/80hiLy6cneg) and spleen monocytes (CD115posLy6chi) were isolated by cell sorting and total RNA from biological triplicates was then isolated according established procedures. We determined the gene expression profiles of MgSCs and how they relate to those of mature microglia and spleen monocytes. This analysis showed how robustly we can identify MgSCs as a separate cell lineage when compared to its closest biological “neighbors”. Importantly, these data sets allowed us to identify signatures of signalling pathways that control the MgSC state needed for regenerating microglia. In addition, we found more surface markers among the differentially expressed genes that define MgSCs, especially we identified human MgSCs and our “proband” marker, Ly6c, does not have a human homolog.