Distinct effects of pharmacological inhibition of stromelysin1 on endothelial‐to‐mesenchymal transition and myofibroblast differentiation

• Published in: Journal of cellular physiology 2021-07, Vol.236 (7), p.5147-5161
• Main Authors: Alharthi, Ahlam, Verma, Arti, Sabbineni, Harika, Adil, Mir S., Somanath, Payaningal R.
• Format: Article
• Language: English
• Subjects: Actin; Activin; Biomarkers; Cadherins; Data analysis; Differentiation; EndMT; Endothelial cells; Fibroblasts; Fibrosis; Gene expression; Kinases; Lung diseases; Matrix metalloproteinase; Mesenchyme; Metalloproteinase; MMP3; Muscles; myofibroblast; Smooth muscle; Stromelysin 1; stromelysin1; Transforming growth factor-b1
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.30221

Endothelial‐to‐mesenchymal transition (EndMT) and fibroblast‐to‐myofibroblast (FibroMF) differentiation are frequently reported in organ fibrosis. Stromelysin1, a matrix metalloprotease‐3 (MMP3) has been indicated in vascular pathologies and organ injuries that often lead to fibrosis. In the current study, we investigated the role of stromelysin1 in EndMT and FibroMF differentiation, which is currently unknown. In our results, whereas TGFβ2 treatment of endothelial cells (ECs) induced EndMT associated with increased expression of stromelysin1 and mesenchymal markers such as α‐smooth muscle actin (αSMA), N‐cadherin, and activin linked kinase‐5 (ALK5), inhibition of stromelysin1 blunted TGFβ2‐induced EndMT. In contrast, treatment of NIH‐3T3 fibroblasts with TGFβ1 promoted FibroMF differentiation accompanied by increased expression of αSMA, N‐cadherin, and ALK5. Intriguingly, stromelysin1 inhibition in TGFβ1‐stimulated myofibroblasts further exacerbated fibroproliferation with increased FibroMF marker expression. Gene Expression Omnibus (GEO) data analysis indicated increased stromelysin1 expression associated with EndMT and decreased stromelysin1 expression in human pulmonary fibrosis fibroblasts. In conclusion, our study has identified that EndMT and FibroMF differentiation are reciprocally regulated by stromelysin1. Endothelial‐to‐mesenchymal transition (EndMT) and fibroblast‐to‐myofibroblast (FibroMF) differentiation contribute to organ fibrosis. Stromelysin1, a matrix metalloprotease‐3 (MMP3) has been indicated in organ injuries and fibrosis. Our study reports that EndMT and FibroMF differentiation are reciprocally regulated by stromelysin1.