Abstract
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.
Highlights
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 parameters analyzed to establish the stability of the model was histopathology and the evaluation of collagen proportionate area (CPA) of the injured tissue
The CPA computed at specific time points of the regeneration in the fibrotic muscle revealed that 50% of the area was covered with collagen on day 2, which escalated to 60% on days 7 and 14
Summary
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 MFs function under the predominant influence of key regulatory pathways like TGF-β, FGF, PDGF and WNT17–22 that have been shown to have pivotal effect on cell proliferation in conjunction with their spectrum of activities in immune response during regeneration. In this investigation we have evaluated the potential of inhibiting MF specific pathways as a therapeutic target to enhance skeletal muscle regeneration by deterring fibrosis. Our study has explored the condition of severe laceration-based muscle injury, with potential to control the outcome of regeneration via MF specific target inhibition. The positive feedback loop of extenuating fibrosis was increased proliferation of SCs and enhanced regeneration
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