Abstract:
In the cornea, the epithelial basement membrane (EBM) and corneal endothelial Descemet\'s basement membrane (DBM) critically regulate the localization, availability and, therefore, the functions of transforming growth factor (TGF)β1, TGFβ2, and platelet-derived growth factors (PDGF) that modulate myofibroblast development. Defective regeneration of the EBM, and notably diminished perlecan incorporation, occurs via several mechanisms and results in excessive and prolonged penetration of pro-fibrotic growth factors into the stroma. These growth factors drive mature myofibroblast development from both corneal fibroblasts and bone marrow-derived fibrocytes, and then the persistence of these myofibroblasts and the disordered collagens and other matrix materials they produce to generate stromal scarring fibrosis. Corneal stromal fibrosis often resolves completely if the inciting factor is removed and the BM regenerates. Similar defects in BM regeneration are likely associated with the development of fibrosis in other organs where perlecan has a critical role in the modulation of signaling by TGFβ1 and TGFβ2. Other BM components, such as collagen type IV and collagen type XIII, are also critical regulators of TGF beta (and other growth factors) in the cornea and other organs. After injury, BM components are dynamically secreted and assembled through the cooperation of neighboring cells-for example, the epithelial cells and keratocytes for the corneal EBM and corneal endothelial cells and keratocytes for the corneal DBM. One of the most critical functions of these reassembled BMs in all organs is to modulate the pro-fibrotic effects of TGFβs, PDGFs and other growth factors between tissues that comprise the organ.
摘要:
在角膜中,上皮基底膜(EBM)和角膜内皮基底膜(DBM)至关重要地调节定位,可用性和,因此,转化生长因子(TGF)β1,TGFβ2和血小板衍生生长因子(PDGF)调节肌成纤维细胞发育的功能。EBM再生缺陷,显著减少了Perlecan的合并,通过几种机制发生,并导致促纤维化生长因子过度和长时间渗透到基质中。这些生长因子驱动成熟的肌成纤维细胞从角膜成纤维细胞和骨髓来源的纤维细胞发育,然后这些肌成纤维细胞和它们产生的无序胶原和其他基质材料的持续存在,从而产生基质瘢痕纤维化。如果去除激发因子并且BM再生,角膜基质纤维化通常会完全解决。BM再生中的类似缺陷可能与其他器官中的纤维化发展有关,其中perlecan在TGFβ1和TGFβ2的信号调节中起关键作用。其他BM组件,如胶原蛋白IV型和胶原蛋白XIII型,也是角膜和其他器官中TGFβ(和其他生长因子)的关键调节剂。受伤后,BM成分通过相邻细胞的合作动态分泌和组装-例如,角膜EBM的上皮细胞和角膜细胞,角膜DBM的角膜内皮细胞和角膜细胞。这些重组的BM在所有器官中最关键的功能之一是调节TGFβs的促纤维化作用,构成器官的组织之间的PDGF和其他生长因子。