International Immunopharmacology · Nov 7, 2026

Decoding the immunoregulatory logic of mesenchymal stromal cells in tissue regeneration: mechanisms, context dependence, and therapeutic translation

By Rezaei M, Behzadifar MM, Tavassoli Razavi F et al.

Mesenchymal stromal cells (MSCs) have attracted increasing attention as therapeutic agents in regenerative medicine because of their immunomodulatory and reparative properties. Increasing evidence indicates that a major component of MSC-mediated tissue repair involves modulation of local immune responses through complex cellular and paracrine interactions rather than direct differentiation into tissue-specific cells. This review provides a mechanistically structured analysis of the biological properties of MSCs and their context-dependent effects on innate and adaptive immune compartments, with particular emphasis on MSC-mediated regulation of T-cell responses, including induction of regulatory T cells, suppression of effector T-cell activity, and emerging but incompletely defined evidence of an exhaustion-like or dysfunction-associated T-cell phenotype characterized by increased expression of inhibitory receptors such as TIM-3. Importantly, we distinguish established immunomodulatory effects from emerging or hypothesis-generating evidence and emphasize that increased inhibitory-receptor expression alone does not establish bona fide T-cell exhaustion. We further examine how MSC–immune cell interactions, including macrophage reprogramming, efferocytosis, and regulation of T-cell and other immune-cell responses, may contribute to inflammatory resolution, angiogenesis, fibrosis control, apoptosis reduction, and endogenous tissue repair. The roles of the MSC secretome, cytokines, growth factors, and extracellular vesicles are critically discussed, with particular attention to the distinction between small extracellular vesicles and exosomes and to methodological factors affecting their functional interpretation. We summarize preclinical and clinical applications of MSC-based therapies across cardiac, hepatic, renal, pulmonary, and neurological disorders, while distinguishing tissue protection and functional improvement from demonstrated restoration of tissue architecture and regeneration. Finally, we discuss next-generation strategies, including genetic engineering, preconditioning, three-dimensional culture, and cell-free approaches, together with key translational challenges related to potency assessment, manufacturing, product heterogeneity, route-specific safety, and clinical implementation. Overall, this review proposes a context-sensitive immunological framework linking MSC-mediated immune regulation to tissue repair, while highlighting the mechanistic uncertainties and evidence gaps that currently limit translation from experimental findings to clinically reproducible regenerative outcomes.

doi.org/10.1016/j.intimp.2026.117656PubMed 42998491Mechanisms