Evasion of apoptosis by myofibroblasts: a hallmark of fibrotic diseases.

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.

器官纤维化是自身免疫性风湿性疾病（如系统性硬化症）的一种致命结局。肌成纤维细胞是形成瘢痕的细胞，它们对纤维化过程中细胞外基质蛋白的过度合成、沉积和重塑负有最终责任。我们对使肌成纤维细胞保持活化状态并控制其功能的机制的理解已经取得了进展。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知之甚少。肌成纤维细胞通过激活分子机制来逃避细胞凋亡，以应对来自纤维化微环境的促存活生物力学和生长因子信号，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并非对细胞凋亡有抵抗力，实际上由于细胞死亡信号通路的同时激活而易于发生细胞凋亡；当存活通路被抑制时，这些细胞就会发生细胞凋亡。这种关于细胞凋亡启动的知识为新的治疗方法铺平了道路，这些治疗方法通过阻断促存活机制在肌成纤维细胞中触发细胞凋亡，以衰老的肌成纤维细胞为靶点诱导其凋亡，或者促进肌成纤维细胞重编程为消除瘢痕的细胞。这些新策略不仅有望防止组织进行性瘢痕形成，而且有可能逆转已形成的纤维化并使慢性受损组织再生。