Depletion of CD206+ M2-like macrophages induces fibro-adipogenic progenitors activation and muscle regeneration
Allah Nawaz, Muhammad Bilal, Shiho Fujisaka, Tomonobu Kado, Muhammad Rahil Aslam, Saeed Ahmed, Keisuke Okabe, Yoshiko Igarashi, Yoshiyuki Watanabe, Takahide Kuwano, Koichi Tsuneyama, Ayumi Nishimura, Yasuhiro Nishida, Seiji Yamamoto, Masakiyo Sasahara, Johji Imura, Hisashi Mori, Martin M. Matzuk, Fujimi Kudo, Ichiro Manabe, Akiyoshi Uezumi, Takashi Nakagawa, Yumiko Oishi, Kazuyuki Tobe
Abstract
Abstract Muscle regeneration requires the coordination of muscle stem cells, mesenchymal fibro-adipogenic progenitors (FAPs), and macrophages. How macrophages regulate the paracrine secretion of FAPs during the recovery process remains elusive. Herein, we systemically investigated the communication between CD206 + M2-like macrophages and FAPs during the recovery process using a transgenic mouse model. Depletion of CD206 + M2-like macrophages or deletion of CD206 + M2-like macrophages-specific TGF-β1 gene induces myogenesis and muscle regeneration. We show that depletion of CD206 + M2-like macrophages activates FAPs and activated FAPs secrete follistatin, a promyogenic factor, thereby boosting the recovery process. Conversely, deletion of the FAP-specific follistatin gene results in impaired muscle stem cell function, enhanced fibrosis, and delayed muscle regeneration. Mechanistically, CD206 + M2-like macrophages inhibit the secretion of FAP-derived follistatin via TGF-β signaling. Here we show that CD206 + M2-like macrophages constitute a microenvironment for FAPs and may regulate the myogenic potential of muscle stem/satellite cells.