Wu Ching-Lung, Lee Gang-Hui, Chen Bo-Yu, Kuo Cheng-Hsiang, Chan Ting-Ting, Wang Yang-Kao, Lin Shuei-Liong, Wong Tzyy-Yue, Tang Ming-Jer
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan.
iScience. 2025 Aug 6;28(9):113317. doi: 10.1016/j.isci.2025.113317. eCollection 2025 Sep 19.
Fibroblasts can be transformed into myofibroblasts under pro-fibrotic conditions, which are characterized by increased contractility and reduced matrix degradation. The relationship between contractile activity and matrix degradation is not fully understood. To mimic physiological conditions, fibroblasts were cultured on a collagen gel with low rigidity. We reveal that a tropomyosin isoform, tropomyosin 1.6 (Tpm1.6), plays a pivotal role in the phenotypic switch upon TGF-β1. Tpm1.6 was specifically upregulated by TGF-β1 in renal fibroblasts. Tpm1.6-silencing decreased TGF-β1-induced myofibroblast markers and contractility, and promoted collagen degradation. Remarkably, in Tpm1.6-silenced fibroblasts, TGF-β1 triggered the formation of distinct α-SMA dots enriched with MMP9, promoting collagen degradation. The targeted silencing of Tpm1.6 in activated myofibroblasts by the induction of promoters of and mitigated unilateral ureteral obstruction-induced renal fibrosis and preserved proximal tubule differentiation. Our study highlights the crucial role of Tpm1.6 in TGF-β1-induced myofibroblast activation and collagen degradation, suggesting a potential therapeutic approach for chronic kidney disease.
在促纤维化条件下，成纤维细胞可转化为肌成纤维细胞，其特征是收缩性增加和基质降解减少。收缩活性与基质降解之间的关系尚未完全明确。为模拟生理条件，将成纤维细胞培养在低刚性的胶原凝胶上。我们发现，一种原肌球蛋白异构体，原肌球蛋白1.6（Tpm1.6），在TGF-β1诱导的表型转换中起关键作用。Tpm1.6在肾成纤维细胞中被TGF-β1特异性上调。沉默Tpm1.6可降低TGF-β1诱导的肌成纤维细胞标志物和收缩性，并促进胶原蛋白降解。值得注意的是，在沉默Tpm1.6的成纤维细胞中，TGF-β1触发了富含MMP9的独特α-SMA点的形成，促进了胶原蛋白降解。通过诱导启动子在活化的肌成纤维细胞中靶向沉默Tpm1.6可减轻单侧输尿管梗阻诱导的肾纤维化，并保留近端小管分化。我们的研究强调了Tpm1.6在TGF-β1诱导的肌成纤维细胞活化和胶原蛋白降解中的关键作用，为慢性肾脏病提示了一种潜在的治疗方法。
