Pulmonary and Critical Care Division, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0130, USA.
Proc Am Thorac Soc. 2012 Jul;9(3):89-95. doi: 10.1513/pats.201112-053AW.
The key role of extracellular matrices in alveolar epithelial cell (AEC) biology is highlighted by the phenotypes of primary AECs cultured on a soft laminin gel contrasted with that on a stiff, fibronectin matrix. On laminin, AECs maintain an epithelial phenotype, and progenitor cells within this population proliferate. In contrast, on fibronectin, AECs rapidly lose surfactant expression and spread extensively, changes that depend on activation of latent TGF-β1 by engagement of fibronectin-binding integrins. The progenitor subpopulation responding to TGF-β1 undergoes epithelial mesenchymal transition (EMT). Although it remains uncertain to what degree EMT contributes directly to collagen 1 production, signaling pathways critical to EMT are important for repair and fibrosis, implying that EMT is part of the general program of lung repair. EMT reprogramming requires not only Smad signaling but also pY654-β-catenin. Generation of pY654-β-catenin requires assembly of complexes of the integrin α3β1, E-cadherin, and TGF-β1 receptors, and such assembly is a function of cell-cell and cell-matrix contacts. Sequestration of α3β1 or E-cadherin in such contacts prevents complex assembly, TGF-β1 induced pY654-β-catenin generation and EMT. Disruption of these contacts is a signal for the cells to initiate repair. Critical remaining questions center around better definition of direct versus indirect effects of EMT on collagen deposition and the nature of AEC progenitors differentiating during fibrogenesis. Elucidation of specific inhibitors of EMT should further test the question of whether the process is important to fibrosis in vivo and a viable therapeutic target.
细胞外基质在肺泡上皮细胞 (AEC) 生物学中的关键作用，通过在软层粘连蛋白凝胶上培养的原代 AEC 与在硬纤连蛋白基质上培养的 AEC 的表型对比得到了强调。在层粘连蛋白上，AEC 保持上皮表型，该细胞群中的祖细胞增殖。相比之下，在纤连蛋白上，AEC 迅速失去表面活性剂表达并广泛扩散，这些变化依赖于纤连蛋白结合整联蛋白激活潜伏的 TGF-β1。对 TGF-β1 有反应的祖细胞亚群经历上皮-间充质转化 (EMT)。虽然 EMT 直接导致胶原 1 产生的程度尚不确定，但 EMT 信号通路对修复和纤维化很重要，这意味着 EMT 是肺修复总体程序的一部分。EMT 重编程不仅需要 Smad 信号，还需要 pY654-β-catenin。pY654-β-catenin 的产生需要整合素 α3β1、E-钙黏蛋白和 TGF-β1 受体的复合物组装，并且这种组装是细胞-细胞和细胞-基质接触的功能。将 α3β1 或 E-钙黏蛋白隔离在这些接触中会阻止复合物组装、TGF-β1 诱导的 pY654-β-catenin 生成和 EMT。这些接触的破坏是细胞开始修复的信号。关键的遗留问题集中在 EMT 对胶原蛋白沉积的直接和间接影响以及在纤维化过程中分化的 AEC 祖细胞的性质上。阐明 EMT 的特定抑制剂应进一步测试该过程是否对体内纤维化很重要以及是否是一个可行的治疗靶点。
