TGF-β1 induces formation of TSG-6-enriched extracellular vesicles in fibroblasts which can prevent myofibroblast transformation by modulating Erk1/2 phosphorylation

• Published in: Scientific reports 2024-05, Vol.14 (1), p.12389-18, Article 12389
• Main Authors: Ilg, Marcus M., Bustin, Stephen A., Ralph, David J., Cellek, Selim
• Format: Article
• Language: English
• Subjects: 631/80; 631/80/304; 631/80/86; 631/80/86/820; Actin; Cell Adhesion Molecules - metabolism; Cell interactions; Cells, Cultured; Erectile dysfunction; Extracellular matrix; Extracellular signal-regulated kinase; Extracellular vesicles; Extracellular Vesicles - metabolism; Fibroblasts; Fibroblasts - metabolism; Genetic transformation; Humanities and Social Sciences; Humans; Male; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; multidisciplinary; Myofibroblasts - metabolism; Pathophysiology; Penile Induration - metabolism; Penile Induration - pathology; Penis; Phosphorylation; Science; Science (multidisciplinary); Signal Transduction; Smad protein; Smooth muscle; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b1
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-62123-x

Extracellular vesicles have emerged as important mediators of cell-to-cell communication in the pathophysiology of fibrotic diseases. One such disease is Peyronie’s disease (PD), a fibrotic disorder of the penis caused by uncontrolled transformation of resident fibroblasts to alpha-smooth muscle actin positive myofibroblasts. These cells produce large amounts of extracellular matrix, leading to formation of a plaque in the penile tunica albuginea (TA), causing pain, penile curvature, and erectile dysfunction. We have used primary fibroblasts derived from the TA of PD patients to explore the role of transforming growth factor beta 1 (TGF-β1), a key signalling factor in this process. TGF-β1 treatment elicited a range of responses from the myofibroblasts: (i) they secreted extracellular vesicles (EVs) that were more numerous and differed in size and shape from those secreted by fibroblasts, (ii) these EVs prevented TGF-β1-induced transformation of fibroblasts in a manner that was dependent on vesicle uptake and (iii) they prevented phosphorylation of Erk1/2, a critical component in modulating fibrogenic phenotypic responses, but did not affect TGF-β1-induced Smad-signalling. We posit that this effect could be linked to enrichment of TSG-6 in myofibroblast-derived EVs. The ability of myofibroblast-derived vesicles to prevent further myofibroblast transformation may establish them as part of an anti-fibrotic negative feedback loop, with potential to be exploited for future therapeutic approaches.