Releasing Tensin.
Releasing Tensin.
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释放张力。
DOI：
10.1165/rcmb.2016-0417ed
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发表时间：
2017
影响因子：
6.4
通讯作者：
Horowitz,JeffreyC
中科院分区：
文献类型：
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作者：
Horowitz,JeffreyC
肌成纤维细胞是修复性细胞，负责细胞外基质（ECM）的合成、分泌、沉积和重塑。在正常伤口修复的背景下，肌成纤维细胞作为必要的效应物发挥作用，有助于旨在恢复组织稳态的综合反应。在肺中，成功的修复反应最终恢复完整的肺泡上皮，降解过量的ECM，并通过细胞凋亡清除肌成纤维细胞，留下不损害肺功能的生理性瘢痕（1）。相比之下，在纤维化肺病如特发性肺纤维化中明显的病理性瘢痕形成的特征部分在于肌成纤维细胞的异常持续。这些流氓肌成纤维细胞无法响应正常的环境信号而关闭，相反，与癌细胞类似，成为病理反应的自主驱动者（2）。我们对成纤维细胞获得这种异常表型的机制的理解继续发展。重要的是，这些机制可能会随着时间的推移而改变，并且最初刺激肌成纤维细胞募集和活化的机制对于它们的存活和持续活化并不是必需的。例如，转化生长因子b1（TGF-b1）因其在体外诱导促纤维化肌成纤维细胞表型和在体内诱导纤维化的能力而被广泛认可。然而，也已经变得明显的是，源自ECM本身的生物力学和生物化学信号可以独立地调节肌成纤维细胞表型和功能（3-5）。因此，描绘机械转导的机制，成纤维细胞将ECM中的环境信号转化为调节其功能的细胞内信号，这对于推进我们对纤维化的机械理解至关重要，并有望开发新的干预措施。MKL-1（巨核细胞白血病-1，也称为Myocardin Related Transcription Factor-A/MRTF-A）是一种转录共激活因子，在静止的成纤维细胞中，与球状肌动蛋白（G-肌动蛋白）结合并隔离在细胞质中。在刺激肌动蛋白聚合的情况下，如暴露于TGF-β或刚性细胞外基质所见，MKL-1从G-肌动蛋白释放并输入细胞核，在那里它与血清反应因子合作以驱动转录反应（6）。这些反应与促纤维化成纤维细胞功能密切相关，因为MKL-1已显示介导成纤维细胞分化、抗凋亡、胶原和纤连蛋白合成以及纤溶酶原激活物抑制剂-1产生（6-8）。在几种鼠模型中，MKL-1的遗传缺陷和MKL-1信号传导的药理学抑制减少了肺纤维化（8-10）。张力蛋白1（Tensin 1，TNS 1）是一种支架蛋白，它通过与整合素b1和定位于细胞粘着斑的蛋白激酶（包括粘着斑激酶（FAK））相互作用，与细胞外纤连蛋白基质的形成和机械传导信号有关。在本期杂志中，Bernau和他的同事们（pp. 465-476）证明了TGF-β 1介导的肌成纤维细胞分化，
Myofibroblasts are reparative cells tasked with the synthesis, secretion, deposition, and remodeling of extracellular matrix (ECM). In the context of normal wound repair, myofibroblasts function as necessary effectors contributing to an integrated response aimed at restoring tissue homeostasis. In the lungs, the successful repair response culminates with restoration of an intact alveolar epithelium, degradation of excessive ECM, and clearance of myofibroblasts via apoptosis, leaving behind a physiologic scar that does not impair lung function (1). In contrast, the pathologic scar formation that is evident in fibrotic lung diseases such as idiopathic pulmonary fibrosis is characterized, in part, by the aberrant persistence of myofibroblasts. These rogue myofibroblasts fail to respond to normal environmental cues to shut down and instead, similar to cancer cells, become autonomous drivers of the pathologic response (2).Our understanding of the mechanisms that underlie fibroblast acquisition of this aberrant phenotype continues to evolve. Importantly, it is possible that these mechanisms change over time and that the mechanisms that initially stimulate myofibroblast recruitment and activation are not required for their survival and persistent activation. Transforming growth factor b1 (TGF-b1), for example, is well recognized for its ability to induce profibrotic myofibroblast phenotypes in vitro and fibrosis in vivo. However, it has also become evident that biomechanical and biochemical signals derived from the ECM itself can independently regulate myofibroblast phenotype and function (3–5). Thus, delineating the mechanisms of mechanotransduction, by which fibroblasts convert environmental cues from the ECM into the intracellular signals that modulate their function is crucial to advancing our mechanistic understanding of fibrosis and holds promise for the development of novel interventions. MKL-1 (megakaryoblastic leukemia-1, also known as Myocardin Related Transcription Factor-A/MRTF-A) is a transcriptional co-activator that is, in quiescent fibroblasts, bound to globular actin (G-actin) and sequestered in the cytoplasm. Under circumstances that stimulate actin polymerization, as seen with exposure to TGF-b or rigid extracellular matrices, MKL-1 is released from G-actin and imported into the nucleus, where it partners with serum response factor to drive transcriptional responses (6). These responses have been strongly linked to profibrotic fibroblast function, as MKL-1 has been shown to mediate fibroblast differentiation, resistance to apoptosis, collagen and fibronectin synthesis, and plasminogen activator inhibitor-1 production (6–8). In several murine models, genetic deficiency in MKL-1 and pharmacologic inhibition of MKL-1 signaling have diminished lung fibrosis (8–10). Tensin1 (TNS1) is a scaffold protein that has been linked to the formation of fibrillary fibronectin matrices and mechanotransduction signaling through its interactions with integrin b1 and protein kinases that localize to cellular focal adhesions, including focal adhesion kinase (FAK). In this issue of the Journal, Bernau and colleagues (pp. 465–476) demonstrate a link among TGF-b1–mediated myofibroblast differentiation,