Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA.
Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA.
Can J Physiol Pharmacol. 2020 Dec;98(12):841-848. doi: 10.1139/cjpp-2020-0123. Epub 2020 Jul 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 with 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.
成纤维细胞向肌成纤维细胞（FibroMF）分化对于胚胎发生和器官纤维化至关重要。尽管转化生长因子-β（TGFβ）是 FibroMF 分化的主要介质，但负责这种作用的 I 型受体（TGFβRI）尚未得到确认。在本研究中，我们研究了 TGFβ1 刺激的 NIH 3T3 成纤维细胞中 ALK1 和 ALK5 的表达，以与基因表达综合数据库（GEO）存储库中的数据进行比较。在我们的结果中，尽管 TGFβ1 处理促进了 FibroMF 分化，伴随着 ALK5 表达的增加和 ALK1 表达的减少，但 ALK5 抑制剂 SB431542 的共同处理抑制了 TGFβ1 诱导的 FibroMF 分化和增加的α-平滑肌肌动蛋白（αSMA）和 ALK5 表达。GEO 数据库分析表明，与正常小鼠或人类组织相比，纤维化组织中 ALK5 表达增加，ALK1 表达减少，这与器官纤维化的进展相关。最后，Akt、mTOR 和 β-连环蛋白抑制剂抑制了 TGFβ1 诱导的 ALK5 表达，表明 Akt 途径通过 ALK5 表达和纤维化促进 FibroMF 分化。
