Resolving Inflammation or Driving Fibrosis: Immune Determinants of Muscle Regenerative Outcomes

Every muscle injury sets in motion a race against time: will the immune system orchestrate a return to fully functional tissue, or will it tip the balance toward scar and dysfunction? This balance, established during the early phases of injury and shaped by the coordinated actions of neutrophils, macrophages, T cells, and fibro-adipogenic progenitors (FAPs), determines whether skeletal muscle undergoes effective regeneration or progresses toward fibrosis. Cracking this puzzle is not just of academic interest: it is central to treating conditions ranging from sports injuries and sarcopenia to muscular dystrophies, where chronic immune dysregulation locks tissue into a fibrotic, non-regenerative state.This Research Topic invites contributions that unpack the cellular and molecular determinants of this balance - macrophage polarization dynamics, neutrophil-macrophage crosstalk, T cell and cytokine signaling, and the immune-FAP-satellite cell axis - across acute versus chronic injury, aging, and dystrophic disease, including cutting-edge single-cell and spatial omics studies that resolve this immune choreography in unprecedented detail.A particular spotlight falls on 3D skeletal muscle models - organoids, tissue-engineered constructs, and organ-on-chip systems - now offering an unprecedented, human-relevant window into immune-muscle crosstalk. By recapitulating key features of the native muscle microenvironment, these systems enable the study of immune cell interactions, inflammation resolution, and disease mechanisms, while supporting the evaluation of regenerative and immunomodulatory strategies. We especially welcome studies benchmarking these next-generation platforms against in vivo and clinical data, helping bridge mechanistic discovery and translational application.Whether your work uncovers a new immune switch, engineers a smarter muscle model, or challenges current paradigms of the inflammation-fibrosis divide, this Research Topic is a home for it. We invite Original Research, Review, Mini Review, and Perspective articles on themes including:• Macrophage polarization and functional plasticity during muscle repair• Fibro-adipogenic progenitor (FAP) regulation by immune signals• T cell and innate lymphoid cell contributions to regeneration versus fibrosis• Cytokine/chemokine networks governing the inflammation-to-resolution transition• Immune dysregulation in muscular dystrophies and chronic myopathies• Immunosenescence and sarcopenia-associated regenerative decline• 3D skeletal muscle models (organoids, bioengineered constructs, organ-on-chip systems) for studying immune-muscle interactions• Mechanical cues, extracellular matrix remodeling, and biomechanical regulation of immune-mediated muscle repair • Patient-derived and personalized 3D muscle models for studying regenerative failure and therapeutic responses• Single-cell/spatial omics approaches to immune niche characterization• Biomaterial and immunomodulatory strategies to promote pro-regenerative immune responses• Biomarkers of regenerative versus fibrotic trajectoriesBy integrating in vivo, ex vivo, and advanced 3D in vitro perspectives, this Research Topic seeks to advance a systems-level understanding of how the immune microenvironment shapes skeletal muscle regenerative outcomes, with the ultimate goal of identifying predictive biomarkers and informing the development of targeted immunomodulatory and regenerative therapies for muscle injury and disease. Topic editors: Federica Cirillo, Marianna Cosentino Source: https://www.frontiersin.org/research-topics/84328/resolving-inflammation-or-driving-fibrosis-immune-determinants-of-muscle-regenerative-outcomes