DPPIV+ fibro-adipogenic progenitors form the niche of adult skeletal muscle self-renewing resident macrophages

Depending on the tissue, adult tissue-resident macrophages (RMs) are either maintained by blood monocytes or through self-renewal at steady state. While the presence of a nurturing-niche is likely crucial to support the survival and function of self-renewing RMs, evidence regarding its nature is limited. Here, we aimed to characterize the niche for skeletal muscle RMs. We found stromal cells called Fibro-Adipogenic Progenitors (FAPs) to be the main source of colony-stimulating factor 1 (CSF1) in resting skeletal muscle. By utilizing parabiosis in combination with transgenic lines that deplete FAPs (PdgfrαCreERT2 ´ DTA) or conditionally delete FAP-derived CSF1 (PdgfrαCreERT2 ´ Csf1flox/null), we showed that local CSF1 from FAPs is required for the survival of both TIM4- monocyte-derived and TIM4+ self-renewing RMs at steady state in adult skeletal muscle. Following pharmacological depletion of RMs, local CSF1 increases significantly to facilitate their replenishment. Indeed, TIM4- RMs get replaced by blood monocytes following depletion and their numbers increase significantly beyond the normal levels. While a noticeable fraction of TIM4+ RMs also gets replaced by blood monocytes following depletion, their numbers are tightly controlled, which indicates the presence of regulatory mechanisms exclusive to TIM4+ cells. The spatial distribution and number of TIM4+ RMs match with a subpopulation of Dipeptidyl peptidase IV (DPPIV)+ FAPs, suggesting their role as nurturing CSF1-producing niche cells for self-renewing RMs. This finding offers novel opportunities to precisely manipulate the function of self-renewing RMs in situ to further unravel their role in health and disease. Characterization of the niche of muscle self-renewing resident macrophages.