Differential regulation of TGFβ type-I receptor expressions in TGFβ1-induced myofibroblast differentiation

Asma Gah, Mir S Adil, Harika Sabbineni, Arti Verma, Payaningal R Somanath
Canadian Journal of Physiology and Pharmacology 2020 July 23
Fibroblast-to-myofibroblast (FibroMF) differentiation is crucial for embryogenesis and organ fibrosis. Although transforming growth factor-β (TGFβ) is the primary mediator of FibroMF differentiation, the type-I receptor (TGFβRI) responsible for this has not yet been confirmed. In the current study, we investigated the ALK1 and ALK5 expressions in TGFβ1-stimulated NIH 3T3 fibroblasts to compare with the data from the gene expression omnibus (GEO) repository. In our results, whereas TGFβ1 treatment promoted FibroMF differentiation accompanied by increased ALK5 expression and reduced ALK1 expression. TGFβ1-induced FibroMF differentiation and increased α-smooth muscle actin (αSMA) and ALK5 expression were inhibited by co-treatment with ALK5 inhibitor SB431542. GEO database analysis indicated increased ALK5 expression and reduced ALK1 expression in fibrotic compared to normal mouse or human tissues correlating to organ fibrosis progression. Finally, the inhibitors of Akt, mTOR, and β-catenin suppressed TGFβ1-induced ALK5 expression indicating that the Akt pathway promotes FibroMF differentiation via ALK5 expression and fibrosis.

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