Microglia actively remodels adult hippocampal neurogenesis through the phagocytosis secretome

During adult hippocampal neurogenesis, the majority of newborn cells undergo apoptosis and are rapidly phagocytosed by resident microglia in order to avoid disturbing the surrounding neurons. Here, we propose that phagocytosis is not merely a passive process of corpse removal but has an active role in maintaining adult hippocampal neurogenesis. First, we found that neurogenesis was disrupted in three defective microglial phagocytosis KO models in vivo (P2Y12, MerTK/Axl , GPR34). We then followed an in vitro approach to perform a transcriptomic analysis of microglial phagocytosis and identified genes involved in metabolism, chromatin remodeling, and neurogenesis-related functions. Finally, we determined that the phagocytic microglia secretome limits the production of new neurons both in vivo and in vitro. Our data suggest that reprogrammed phagocytic microglia acts as a sensor of local cell death, modulating the balance between cell proliferation and cell survival in the neurogenic niche, supporting the long-term maintenance of adult hippocampal neurogenesis. We performed a mouse-specific full genome-wide transcriptomic analysis using gene expression mouse-specific arrays comparing naïve vs. phagocytic microglia. We developed a xenogeneic in vitro model of phagocytosis of apoptotic cells (Beccari et al., 2018), in which mouse primary microglia were fed for two different time points (3 and 24h) with a human neuronal line (SH-SY5Y), previously labeled with CM-DiI and treated with staurosporine (STP; 4h, 3µM) for apoptosis induction. The experiment was performed in the presence of a control group of naïve microglia which were not exposed to any phagocytic stimuli. N=3 independent experiments were performed for this transcriptomic analysis.