Stem Cell Biology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, 110067, India.
, Abi Nivas, Subbanapalya Extension, Bangalore, 560043, India.
Sci Rep. 2021 Jan 8;11(1):63. doi: 10.1038/s41598-020-79771-4.
Aberrant regeneration or fibrosis in muscle is the denouement of deregulated cellular and molecular events that alter original tissue architecture due to accumulation of excessive extracellular matrix. The severity of the insult to the skeletal muscle determines the nature of regeneration. Numerous attempts at deciphering the mechanism underlying fibrosis and the subsequent strategies of drug therapies have yielded temporary solutions. Our intent is to understand the interaction between the myofibroblasts (MFs) and the satellite cells (SCs), during skeletal muscle regeneration. We hypothesize that MFs contribute to the impairment of SCs function by exhibiting an antagonistic influence on their proliferation. A modified laceration based skeletal muscle injury model in mouse was utilized to evaluate the dynamics between the SCs and MFs during wound healing. We show that the decline in MFs' number through inhibition of PDGFRα signaling consequently promotes proliferation of the SCs and exhibits improved skeletal muscle remodeling. We further conclude that in situ administration of PDGFRα inhibitor prior to onset of fibrosis may attenuate aberrant regeneration. This opens new possibility for the early treatment of muscle fibrosis by specific targeting of MFs rather than transplantation of SCs.
肌肉中的异常再生或纤维化是细胞和分子事件失调的结果，这些事件会因细胞外基质的过度积累而改变原始组织结构。骨骼肌受到的损伤的严重程度决定了再生的性质。人们为了解纤维化的机制以及随后的药物治疗策略做出了许多尝试，但都只是暂时的解决方案。我们的目的是了解肌成纤维细胞（MFs）和卫星细胞（SCs）在骨骼肌再生过程中的相互作用。我们假设 MFs 通过对其增殖表现出拮抗作用，从而导致SCs 功能受损。我们利用改良的基于撕裂的小鼠骨骼肌损伤模型来评估在伤口愈合过程中SCs 和 MFs 之间的动态变化。我们发现，通过抑制 PDGFRα 信号来减少 MFs 的数量，会促进SCs 的增殖，并改善骨骼肌重塑。我们进一步得出结论，在纤维化开始之前在原位给予 PDGFRα 抑制剂可能会减轻异常再生。这为通过特异性靶向 MFs 而不是移植SCs 来早期治疗肌肉纤维化提供了新的可能性。
