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

Abstract Adult tissue-resident macrophages (RMs) are either maintained by blood monocytes or through self-renewal. 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 identify fibro-adipogenic progenitors (FAPs) as the main source of colony-stimulating factor 1 (CSF1) in resting skeletal muscle. Using parabiosis in combination with FAP-deficient transgenic mice ( Pdgfrα CreERT2 × DTA) or mice lacking FAP-derived CSF1 ( Pdgfrα CreERT2 × Csf1 flox/null ), we show that local CSF1 from FAPs is required for the survival of both TIM4 - monocyte-derived and TIM4 + self-renewing RMs in adult skeletal muscle. The spatial distribution and number of TIM4 + RMs coincide with those of dipeptidyl peptidase IV (DPPIV) + FAPs, suggesting their role as CSF1-producing niche cells for self-renewing RMs. This finding identifies opportunities to precisely manipulate the function of self-renewing RMs in situ to further unravel their role in health and disease.