Microglial network organization: A context-dependent interplay between self-renewal, clonal expansion and resolution.
Microglia constitute a highly specialized network of tissue-resident immune cells that is important for modulating central nervous system (CNS) development, maintaining tissue homeostasis and resolving injury and diseases in the brain. Little is known about how their spatial distribution is established and maintained in vivo throughout the lifespan of the organism. Using novel microglia-specific mouse models for fate mapping and clonal analysis, we found that microglia establish a dense network with regional differences. The variable rates of turnover also challenge the universal concept of microglial longevity. Slow microglial renewal (0.08 % − 0.4 % per day) was observed in a stochastic manner across the brain regions. In contrast, targeted clonal expansion occurs rapidly (~700 % within 7 days) in response to neurodegeneration. Notably, we identified the dual mechanism of cell emigration and local apoptosis for re-establishing healthy microglial cell density during CNS recovery. Single-cell RNA-sequencing and comparative transcriptomic analysis revealed neurodegeneration- and recovery-associated microglial gene signatures. Genetic regulation of cell migration, interferon response and lipid mediation in microglial cells were implicated in the recovery process. By defining the mechanisms through which steady state conformation of microglia is achieved, we can unveil molecular targets that promote recovery and reduce chronic inflammatory responses in CNS diseases.
Short bio: loop.frontiersin.org/people/502442/bio