Mesenchymal Stem Cell Therapy for Systemic Sclerosis: Current Evidence and Clinical Applications.

Systemic sclerosis is a multisystem autoimmune disease characterized by immune dysfunction, vasculopathy, and progressive fibrosis, yet current therapies rarely address these pathogenic axes simultaneously. Mesenchymal stem cell therapy has gained increasing interest as a disease-modifying strategy because its therapeutic activity appears to depend largely on paracrine signaling rather than durable engraftment. Through these mechanisms, mesenchymal stem cells may suppress profibrotic fibroblast activation, recalibrate innate and adaptive immune responses, and enhance vascular repair. Cell-free approaches, particularly extracellular vesicles and exosome-based therapeutics, are further expanding the translational potential of this field by offering scalable alternatives to live cell administration. Early clinical studies of systemic infusion and local delivery for complications such as hand dysfunction (reduced grip strength, joint contracture, and impaired fine motor function) and digital vasculopathy have demonstrated feasibility, acceptable short-term safety, and encouraging signals in skin and vascular outcomes. Nevertheless, long term clinical benefit remains uncertain because published studies are few and heterogeneous in cell source, manufacturing and expansion protocols, dose, route, concomitant therapy, and endpoint selection. Progress in this area will require standardized potency frameworks, improved control of senescence and functional drift, phenotype-specific trial stratification, and harmonized outcome hierarchies across vascular and cutaneous domains. Integration of immune and vascular biomarkers as pharmacodynamic readouts, together with multicenter randomized controlled trials and long-term follow-up, will be essential for defining efficacy and advancing targeted cell-free therapeutic platforms in systemic sclerosis.