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.