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.

Although macrophages infiltrating the skeletal muscles are known to be important in muscle growth and repair, much less is known about muscle-resident macrophages. Here, the authors identify a fibro-adipogenic progenitor niche involved in the maintenance of skeletal muscle-resident macrophages.