Redhead Charlene, Taye Nandaraj, Chin-Young Britney, Oguntuyo Kasoorelope, Cummins James H, Hart Kevin J, Han Woojin M, Hubmacher Dirk
Orthopedic Research Laboratories, Leni & Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
iScience. 2025 May 20;28(6):112712. doi: 10.1016/j.isci.2025.112712. eCollection 2025 Jun 20.
Skeletal muscle development and regeneration requires the activities of myogenic and non-myogenic muscle stem cell populations. Non-myogenic muscle stem cells, such as fibro-adipogenic progenitors (FAPs), play important roles in muscle regeneration after injury. Activated FAPs promote myogenic muscle stem cell differentiation and contribute to the restoration of muscle architecture. In pathological conditions, FAPs can differentiate into adipocytes or fibroblasts, causing fatty infiltrations or muscle fibrosis, respectively. Here, we identified the extracellular matrix protein ADAMTS-like 2 () as a regulator of adipogenic and fibrogenic FAP differentiation. In the context of fibrogenic FAP differentiation, ADAMTSL2 inhibited the differentiation of primary mouse and human FAPs into fibroblasts in a transforming growth factor β (TGF-β)-dependent manner. Together with our previous data, a model emerges where ADAMTSL2 has a dual role in skeletal muscle biology, a pro-myogenic role, where ADAMTSL2 promotes myogenic muscle stem cell differentiation, and a TGF-β-dependent anti-fibrotic role where ADAMTSL2 attenuates FAP-to-fibroblast differentiation.
骨骼肌的发育和再生需要肌源性和非肌源性肌肉干细胞群体的活动。非肌源性肌肉干细胞，如成纤维脂肪生成祖细胞（FAPs），在损伤后的肌肉再生中发挥重要作用。活化的FAPs促进肌源性肌肉干细胞分化，并有助于肌肉结构的恢复。在病理条件下，FAPs可分别分化为脂肪细胞或成纤维细胞，导致脂肪浸润或肌肉纤维化。在这里，我们确定细胞外基质蛋白类含金属蛋白酶解聚素样2（ADAMTSL2）是脂肪生成和成纤维FAP分化的调节因子。在成纤维FAP分化的背景下，ADAMTSL2以转化生长因子β（TGF-β）依赖的方式抑制原代小鼠和人FAPs向成纤维细胞的分化。结合我们之前的数据，出现了一个模型，其中ADAMTSL2在骨骼肌生物学中具有双重作用，即促肌源性作用，ADAMTSL2促进肌源性肌肉干细胞分化；以及TGF-β依赖的抗纤维化作用，ADAMTSL2减弱FAP向成纤维细胞的分化。
