Mesenchymal Stem Cells Modulate Regulatory T Cells: From Molecular Mechanisms to Disease Therapy
Mesenchymal stem cells (MSCs) and regulatory T cells (Tregs) form a key immunoregulatory axis essential for maintaining immune homeostasis and treating autoimmune diseases, transplant rejection, and inflammatory disorders. Although both MSCs and Tregs have been individually studied, a clear synthesis of how MSCs regulate Treg function across distinct mechanistic layers and disease contexts remains lacking. MSCs regulate Treg differentiation, expansion, and functional stability through paracrine signaling, intercellular contact–dependent pathways, extracellular vesicle (EV)–mediated transfer of microRNAs (miRNAs) and proteins, mitochondrial transfer, and metabolic and epigenetic reprogramming. These mechanisms restore Th17/Treg balance, suppress inflammation, and promote tissue repair. Preclinical studies demonstrate strong therapeutic potential in multiple immune–mediated diseases; however, clinical translation remains limited. Unlike previous studies, this review integrates soluble and exosomal signaling pathways, compares shared and disease‐specific regulatory mechanisms, and critically evaluates MSC source variability, methodological limitations, and causes of clinical inconsistency. It aims to provide a conceptual framework to guide future mechanistic studies and clinical development of MSC–Treg–based therapies.