Regenerative Engineering of Fibrotic Diseases: Mechanistic and Clinical Advances with Bone Marrow Mesenchymal Stem Cells

Bone marrow-derived mesenchymal stem cells (BM-MSCs) have demonstrated significant potential owing to their strong immunomodulatory, anti-inflammatory, and regenerative properties. This review explores the antifibrotic effects of BM-MSCs, focusing on their underlying mechanisms, preclinical evidence, and progress in clinical trials. BM-MSCs moderate fibrosis through immune modulation, regulation of myofibroblast differentiation, and stimulation of matrix metalloproteinase (MMP)-mediated degradation of the extracellular matrix (ECM). In pulmonary fibrosis animal models, BM-MSCs reduced TGF-β1 activation and α-SMA and improved lung histology under experimental conditions; some studies included corticosteroid-treated comparators. Additionally, BM-MSCs inhibited the activation of hepatic stellate cells and promoted the polarization of macrophages to an M2 anti-inflammatory phenotype in liver fibrosis. Genetically modified bone marrow-derived mesenchymal stem cells (GM BM-MSCs), such as those transfected with miRNA or overexpressing IL-10, have demonstrated enhanced efficacy in ameliorating myocardial and renal fibrosis through increased homing, paracrine functions, and the inhibition of fibrosis-promoting genes. Early clinical trials of idiopathic pulmonary fibrosis and cirrhotic conditions have indicated their feasibility, safety, and potential efficacy. BM-MSC-derived extracellular vesicles (EVs) provide cell-free therapeutic alternatives with comparable benefits to those of BM-MSCs. Overall, this review provides a comprehensive mechanistic overview of the antifibrotic potential of BM-MSCs, highlighting their translational relevance across organ systems and their promise in regenerative medicine.