Integrin β1 Establishes Liver Microstructure and Modulates Transforming Growth Factor β during Liver Development and Regeneration
Integrin β1 Establishes Liver Microstructure and Modulates Transforming Growth Factor β during Liver Development and Regeneration
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DOI：
10.1016/j.ajpath.2020.10.011
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发表时间：
2021-01-29
影响因子：
6
通讯作者：
Karp, Seth J.
中科院分区：
文献类型：
--
作者：
Masuzaki, Ryota;Ray, Kevin C.;Karp, Seth J.
独特而复杂的显微结构是肝脏不同功能的基础。这种组织的破坏，就像在纤维化和肝硬变中发生的那样，损害肝功能并导致疾病。研究了整合素β1在建立肝脏微结构和损伤后重建肝脏微结构中的作用。肝脏中整合素β1的胚胎缺失破坏了肝细胞的正常发育、细胞-细胞连接的规范和小管的形成。这进而导致转化生长因子-β(TGF-β)的表达和广泛的纤维化。靶向删除成人肝细胞中的整合素β可阻止肝损伤后正常肝细胞结构的重建，从而导致纤维化。在体外，整合素RID对于小管的形成是必不可少的，也是通过调节转化生长因子-β来防止星状细胞激活所必需的。综上所述，这些发现确认整合素β1是肝脏结构的关键决定因素，具有调节转化生长因子β1分泌的关键作用。这些结果表明，破坏肝细胞-细胞外基质的相互作用足以推动纤维化。
A unique and complex microstructure underlies the diverse functions of the liver. Breakdown of this organization, as occurs in fibrosis and cirrhosis, impairs liver function and leads to disease. The role of integrin beta 1 was examined both in establishing liver microstructure and recreating it after injury. Embryonic deletion of integrin beta 1 in the liver disrupts the normal development of hepatocyte polarity, specification of cell-cell junctions, and canalicular formation. This in turn leads to the expression of transforming growth factor beta (TGF-beta) and widespread fibrosis. Targeted deletion of integrin beta in adult hepatocytes prevents recreation of normal hepatocyte architecture after liver injury, with resultant fibrosis. In vitro, integrin rid is essential for canalicular formation and is needed to prevent stellate cell activation by modulating TGF-beta. Taken together, these findings identify integrin beta 1 as a key determinant of liver architecture with a critical role as a regulator of TGF-beta 1 secretion. These results suggest that disrupting the hepatocyte-extracellular matrix interaction is sufficient to drive fibrosis.