Organ fibrosis is a lethal outcome of autoimmune rheumatic diseases such as systemic sclerosis. Myofibroblasts are scar-forming cells that are ultimately responsible for the excessive synthesis, deposition and remodelling of extracellular matrix proteins in fibrosis. Advances have been made in our understanding of the mechanisms that keep myofibroblasts in an activated state and control myofibroblast functions. However, the mechanisms that help myofibroblasts to persist in fibrotic tissues remain poorly understood. Myofibroblasts evade apoptosis by activating molecular mechanisms in response to pro-survival biomechanical and growth factor signals from the fibrotic microenvironment, which can ultimately lead to the acquisition of a senescent phenotype. Growing evidence suggests that myofibroblasts and senescent myofibroblasts, rather than being resistant to apoptosis, are actually primed for apoptosis owing to concomitant activation of cell death signalling pathways; these cells are poised to apoptose when survival pathways are inhibited. This knowledge of apoptotic priming has paved the way for new therapies that trigger apoptosis in myofibroblasts by blocking pro-survival mechanisms, target senescent myofibroblast for apoptosis or promote the reprogramming of myofibroblasts into scar-resolving cells. These novel strategies are not only poised to prevent progressive tissue scarring, but also have the potential to reverse established fibrosis and to regenerate chronically injured tissues.

中文翻译：

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肌成纤维细胞逃避细胞凋亡：纤维化疾病的标志。

器官纤维化是自身免疫性风湿性疾病如系统性硬化症的致命结果。肌成纤维细胞是形成瘢痕的细胞，最终导致纤维化中细胞外基质蛋白的过度合成、沉积和重塑。我们对使肌成纤维细胞保持活化状态和控制肌成纤维细胞功能的机制的理解取得了进展。然而，帮助肌成纤维细胞在纤维化组织中持续存在的机制仍然知之甚少。肌成纤维细胞通过响应来自纤维化微环境的促生存生物力学和生长因子信号激活分子机制来逃避细胞凋亡，这最终可能导致获得衰老表型。越来越多的证据表明，肌成纤维细胞和衰老的肌成纤维细胞，由于伴随的细胞死亡信号通路的激活，而不是抵抗细胞凋亡，实际上是为细胞凋亡做好准备；当生存途径被抑制时，这些细胞准备凋亡。这种关于凋亡启动的知识为新疗法铺平了道路，这些新疗法通过阻断促存活机制、靶向衰老的肌成纤维细胞进行细胞凋亡或促进肌成纤维细胞重编程为疤痕解决细胞来触发肌成纤维细胞的细胞凋亡。这些新策略不仅可以防止进行性组织瘢痕形成，而且有可能逆转已建立的纤维化并再生慢性损伤组织。当生存途径被抑制时，这些细胞准备凋亡。这种关于凋亡启动的知识为新疗法铺平了道路，这些新疗法通过阻断促存活机制、靶向衰老的肌成纤维细胞进行细胞凋亡或促进肌成纤维细胞重编程为疤痕解决细胞来触发肌成纤维细胞的细胞凋亡。这些新策略不仅可以防止进行性组织瘢痕形成，而且有可能逆转已建立的纤维化并再生慢性损伤组织。当生存途径被抑制时，这些细胞准备凋亡。这种关于凋亡启动的知识为新疗法铺平了道路，这些新疗法通过阻断促存活机制、靶向衰老的肌成纤维细胞进行细胞凋亡或促进肌成纤维细胞重编程为疤痕解决细胞来触发肌成纤维细胞的细胞凋亡。这些新策略不仅可以防止进行性组织瘢痕形成，而且有可能逆转已建立的纤维化并再生慢性损伤组织。