Targeting C1q signaling in fibro-adipogenic progenitors prevents regenerative fibrosis of aged muscle

Skeletal muscle fibrosis, as occurs with age, in response to injury, or in the setting of degenerative diseases, results in impairments of muscle regeneration and function. Fibroadipogenic progenitors (FAPs), a distinct population of muscle-resident mesenchymal progenitor cells that reside in muscle interstitium, play a crucial role in normal muscle regeneration by supporting muscle stem cell proliferation. However, in pathological conditions such as severe or recurrent muscle injury, FAPs can aberrantly differentiate into fibrogenic cells, resulting in excessive deposition of extracellular matrix and fibrosis. In this study, we explore the molecular regulation of FAP differentiation along the fibrogenic lineage to gain insights into the mechanisms of fibrosis in aged muscle in response to injury. Our findings reveal that aging is associated with an increased expression of the complement Component 1q (C1q) in muscle-resident macrophages and elevated expression of the complement proteins C1r and C1s in FAPs. Exposure of proliferating FAPs to C1q results in the activation of the Wnt signaling pathway, elevated expression of collagen genes, and FAP fibrogenic differentiation, leading to increased tissue fibrosis. We demonstrate that either pharmacological inhibition of the complement pathway or genetic ablation of C1s in FAPs in aged mice reduces fibrogenic differentiation of FAPs by suppressing Wnt signaling. This reduction in FAP differentiation attenuates the fibrotic response to injury in aged animals as well as in a mouse model of muscular dystrophy. Our study supports the inhibition of complement signaling as a potential therapeutic strategy for mitigating fibrosis in skeletal muscle injury or degeneration. Overall design: Fibroadipogenic progenitors from mouse skeletal muscles were treated with control or C1q and subjected to bulk-RNA seq analysis.

骨骼肌纤维化（skeletal muscle fibrosis）是伴随衰老、损伤应答或退行性疾病发生的病变，会损害肌肉再生能力与生理功能。纤维脂肪祖细胞（fibroadipogenic progenitors, FAPs）是一类定居于肌肉间质的独特肌肉驻留间充质祖细胞群，通过支持肌肉干细胞增殖在正常肌肉再生过程中发挥关键作用。然而在严重或复发性肌肉损伤等病理状态下，FAPs会异常分化为成纤维细胞，引发细胞外基质过度沉积并最终导致纤维化。
本研究旨在探究FAPs沿成纤维细胞谱系分化的分子调控机制，以解析衰老肌肉在损伤应答中的纤维化发生机制。研究结果显示，衰老会使肌肉驻留巨噬细胞的补体成分1q（complement Component 1q, C1q）表达上调，同时上调FAPs中补体蛋白C1r与C1s的表达水平。将增殖状态的FAPs暴露于C1q环境中，可激活Wnt信号通路、上调胶原基因表达，并诱导FAPs向成纤维细胞分化，最终加剧组织纤维化程度。
本研究证实，在衰老小鼠中，无论是通过药理学手段抑制补体通路，还是在FAPs中敲除C1s基因，均可通过抑制Wnt信号通路减弱FAPs的成纤维分化能力。这种FAP分化的抑制作用，能够减轻衰老动物以及肌营养不良小鼠模型中损伤诱导的纤维化反应。本研究支持补体信号抑制可作为缓解骨骼肌损伤或退行性病变相关纤维化的潜在治疗策略。
整体实验设计：从小鼠骨骼肌中分离纤维脂肪祖细胞，分别以对照试剂或C1q进行处理，随后开展批量RNA测序（bulk-RNA seq）分析。