Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, 1530 3rd Avenue South, Birmingham, AL 35294, USA
Exp Cell Res. 2011 Aug 1;317(13):1914-21. doi: 10.1016/j.yexcr.2011.03.016. Epub 2011 Apr 1.
Myofibroblasts participate in tissue repair processes in diverse mammalian organ systems. The deactivation of myofibroblasts is critical for termination of the reparative response and restoration of tissue structure and function. The current paradigm on normal tissue repair is the apoptotic clearance of terminally differentiated myofibroblasts; while, the accumulation of activated myofibroblasts is associated with progressive human fibrotic disorders. The capacity of myofibroblasts to undergo de-differentiation as a potential mechanism for myofibroblast deactivation has not been examined. In this report, we have uncovered a role for MyoD in the induction of myofibroblast differentiation by transforming growth factor-β1 (TGF-β1). Myofibroblasts demonstrate the capacity for de-differentiation and proliferation by modulation of endogenous levels of MyoD. We propose a model of reciprocal signaling between TGF-β1/ALK5/MyoD and mitogen(s)/ERK-MAPK/CDKs that regulate myofibroblast differentiation and de-differentiation, respectively. Our studies provide the first evidence for MyoD in controlling myofibroblast activation and deactivation. Restricted capacity for de-differentiation of myofibroblasts may underlie the progressive nature of recalcitrant human fibrotic disorders.
肌成纤维细胞参与多种哺乳动物器官系统的组织修复过程。肌成纤维细胞的失活对于修复反应的终止和组织结构及功能的恢复至关重要。目前关于正常组织修复的模式是终末分化的肌成纤维细胞的凋亡清除；而激活的肌成纤维细胞的积累与进行性人类纤维化疾病有关。肌成纤维细胞去分化的能力作为肌成纤维细胞失活的潜在机制尚未被研究。在本报告中，我们发现 MyoD 在转化生长因子-β1 (TGF-β1)诱导肌成纤维细胞分化中起作用。肌成纤维细胞通过调节内源性 MyoD 水平显示出去分化和增殖的能力。我们提出了一个 TGF-β1/ALK5/MyoD 和有丝分裂原/ERK-MAPK/CDKs 之间的相互信号转导模型，分别调节肌成纤维细胞的分化和去分化。我们的研究首次为 MyoD 控制肌成纤维细胞的激活和失活提供了证据。肌成纤维细胞去分化的能力受限可能是难治性人类纤维化疾病进行性的基础。
