Department of Pharmacology, Faculty of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807-8555, Japan.
Department of Pharmacology, Faculty of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807-8555, Japan.
Biochem Pharmacol. 2023 Aug;214:115663. doi: 10.1016/j.bcp.2023.115663. Epub 2023 Jun 17.
Fibrosis occurs in all organs and tissues except the brain, and its progression leads to dysfunction of affected organs. Fibrosis-induced organ dysfunction results from the loss of elasticity, strength, and functionality of tissues due to the extracellular matrix secreted by myofibroblasts that express smooth muscle-type actin as a marker. Myofibroblasts, which play a major role in fibrosis, were once thought to originate exclusively from activated fibroblasts; however, it is now clear that myofibroblasts are diverse in origin, from epithelial cells, endothelial cells, adipocytes, macrophages, and other cells. Fibrosis of vital organs, such as the heart, lungs, kidneys, and liver, is a serious chronic disease that ultimately leads to death. Currently, anti-cancer drugs have made remarkable progress, as evidenced by the development of many molecular-targeted drugs, and are making a significant contribution to improving the prognosis of cancer treatment. However, the development of anti-fibrotic agents, which also play an important role in prognosis, has lagged. In this review, the current knowledge regarding myofibroblasts is summarized, with particular attention given to their origin and transdifferentiation signaling pathways (e.g., TGF-β, Wnt/β-catenin, YAP/TAZ and AMPK signaling pathways). The development of new small molecule anti-fibrotic agents and the repositioning of existing drugs targeting myofibroblast transdifferentiation are discussed.
纤维化发生于除大脑以外的所有器官和组织，其进展导致受影响器官的功能障碍。纤维化诱导的器官功能障碍是由于肌成纤维细胞分泌的细胞外基质导致组织失去弹性、强度和功能所致，肌成纤维细胞以平滑肌肌动蛋白作为标志物表达。肌成纤维细胞在纤维化中起主要作用，曾被认为仅起源于活化的成纤维细胞；然而，现在很清楚，肌成纤维细胞来源多样，包括上皮细胞、内皮细胞、脂肪细胞、巨噬细胞和其他细胞。心脏、肺、肾和肝等重要器官的纤维化是一种严重的慢性疾病，最终导致死亡。目前，抗癌药物取得了显著进展，许多分子靶向药物的开发就是明证，它们为改善癌症治疗预后做出了重大贡献。然而，抗纤维化药物的开发却滞后了，这类药物在预后中也起着重要作用。在这篇综述中，总结了肌成纤维细胞的现有知识，特别关注了它们的起源和转分化信号通路（例如 TGF-β、Wnt/β-catenin、YAP/TAZ 和 AMPK 信号通路）。讨论了新型小分子抗纤维化药物的开发以及针对肌成纤维细胞转分化的现有药物的再定位。
