Persistent myofibroblast activation distinguishes pathological fibrosis from physiological wound healing, suggesting that therapies selectively inducing myofibroblast apoptosis could prevent progression and potentially reverse established fibrosis in diseases such as scleroderma, a heterogeneous autoimmune disease characterized by multiorgan fibrosis. We demonstrate that fibroblast-to-myofibroblast differentiation driven by matrix stiffness increases the mitochondrial priming (proximity to the apoptotic threshold) of these activated cells. Mitochondria in activated myofibroblasts, but not quiescent fibroblasts, are primed by death signals such as the proapoptotic BH3-only protein BIM, which creates a requirement for tonic expression of the antiapoptotic protein BCL-X_L to sequester BIM and ensure myofibroblast survival. Myofibroblasts become particularly susceptible to apoptosis induced by “BH3 mimetic” drugs inhibiting BCL-X_L such as ABT-263. ABT-263 displaces BCL-X_L binding to BIM, allowing BIM to activate apoptosis on stiffness-primed myofibroblasts. Therapeutic blockade of BCL-X_L with ABT-263 (navitoclax) effectively treats established fibrosis in a mouse model of scleroderma dermal fibrosis by inducing myofibroblast apoptosis. Using a BH3 profiling assay to assess mitochondrial priming in dermal fibroblasts derived from patients with scleroderma, we demonstrate that the extent of apoptosis induced by BH3 mimetic drugs correlates with the extent of their mitochondrial priming, indicating that BH3 profiling could predict apoptotic responses of fibroblasts to BH3 mimetic drugs in patients with scleroderma. Together, our findings elucidate the potential efficacy of targeting myofibroblast antiapoptotic proteins with BH3 mimetic drugs in scleroderma and other fibrotic diseases.

持续的肌成纤维细胞激活将病理性纤维化与生理性伤口愈合区分开来，这表明选择性诱导肌成纤维细胞凋亡的疗法可以预防进展并可能逆转疾病中已建立的纤维化，例如硬皮病，一种以多器官纤维化为特征的异质性自身免疫性疾病。我们证明了由基质刚度驱动的成纤维细胞到肌成纤维细胞的分化增加了这些活化细胞的线粒体启动（接近凋亡阈值）。激活的肌成纤维细胞中的线粒体，而不是静止的成纤维细胞，由死亡信号引发，例如促凋亡 BH3-only 蛋白 BIM，这为抗凋亡蛋白 BCL-X _{L 的}强直表达创造了条件隔离 BIM 并确保肌成纤维细胞存活。肌成纤维细胞变得特别容易受到抑制 BCL-X _L的“BH3 模拟物”药物（如 ABT-263）诱导的细胞凋亡的影响。ABT-263 取代 BCL-X _L与 BIM 的结合，允许 BIM 激活硬化引发的肌成纤维细胞的细胞凋亡。BCL-X _{L 的}治疗性阻断使用 ABT-263（navitoclax）通过诱导肌成纤维细胞凋亡有效治疗硬皮病真皮纤维化小鼠模型中已建立的纤维化。使用 BH3 分析测定评估源自硬皮病患者的真皮成纤维细胞中的线粒体启动，我们证明 BH3 模拟药物诱导的细胞凋亡程度与其线粒体启动的程度相关，表明 BH3 分析可以预测成纤维细胞的凋亡反应硬皮病患者的 BH3 模拟药物。总之，我们的研究结果阐明了在硬皮病和其他纤维化疾病中使用 BH3 模拟药物靶向肌成纤维细胞抗凋亡蛋白的潜在功效。