Cole Eye Institute, I-32, Cleveland Clinic, 9500, Euclid Ave, Cleveland, OH, United States.
Cole Eye Institute, I-32, Cleveland Clinic, 9500, Euclid Ave, Cleveland, OH, United States.
Exp Eye Res. 2021 Jan;202:108303. doi: 10.1016/j.exer.2020.108303. Epub 2020 Oct 14.
The unwounded, normal corneal stroma is a relatively simple, avascular tissue populated with quiescent keratocytes, along with corneal nerves and a few resident dendritic and monocyte/macrophage cells. In the past, the resting keratocytes were thought of as a homogenous cellular population, but recent work has shown local variations in vimentin and nestin expression, and responsiveness to transforming growth factor (TGF)-β1. Studies have also supported there being "stromal stem cells" in localized areas. After corneal wounding, depending on the site and severity of injury, profound changes in stromal cellularity occur. Anterior or posterior injuries to the epithelium or endothelium, respectively, trigger apoptosis of adjacent keratocytes. Many contiguous keratocytes transition to keratocan-negative corneal fibroblasts that are proliferative and produce limited amounts of disorganized extracellular matrix components. Simultaneously, large numbers of bone marrow-derived cells, including monocytes, neutrophils, fibrocytes and lymphocytes, invade the stroma from the limbal blood vessels. Ongoing adequate levels of TGFβ1, TGFβ2 and platelet-derived growth factor (PDGF) from epithelium, tears, endothelium and aqueous humor that penetrate defective or absent epithelial barrier function (EBF) and epithelial basement membrane (EBM) and/or Descemet's basement membrane (DBM) drive corneal fibroblasts and fibrocytes to differentiate into alpha-smooth muscle actin (SMA)-positive myofibroblasts. If the EBF, EBM and/or DBM are repaired or replaced in a timely manner, typically measured in weeks, then corneal fibroblast and fibrocyte progeny, deprived of requisite levels of TGFβ1 and TGFβ2, undergo apoptosis or revert to their precursor cell-types. If the EBF, EBM and/or DBM are not repaired or replaced, stromal levels of TGFβ1 and TGFβ2 remain elevated, and mature myofibroblasts are generated from corneal fibroblasts and fibrocyte precursors that produce prodigious amounts of disordered extracellular matrix materials associated with scarring fibrosis. This fibrotic stromal matrix persists, at least until the EBF, EBM and/or DBM are regenerated or replaced, and keratocytes remove and reorganize the affected stromal matrix.
未受伤的正常角膜基质是一种相对简单、无血管的组织，其中充满静止的角膜基质细胞，以及角膜神经和少量常驻树突状细胞和单核/巨噬细胞。过去，静止的角膜基质细胞被认为是同质的细胞群体，但最近的研究表明，波形蛋白和巢蛋白的表达存在局部差异，并且对转化生长因子 (TGF)-β1 有反应。研究还支持在局部区域存在“基质干细胞”。角膜受伤后，根据损伤的部位和严重程度，基质细胞数量会发生深刻变化。分别损伤上皮或内皮的前部或后部，会引发相邻角膜基质细胞的凋亡。许多相邻的角膜基质细胞转化为角膜蛋白阴性的角膜成纤维细胞，这些细胞增殖并产生有限数量的无序细胞外基质成分。同时，大量骨髓来源的细胞，包括单核细胞、中性粒细胞、成纤维细胞和淋巴细胞，从角膜缘血管侵入基质。来自上皮、泪液、内皮和房水的持续足够水平的 TGFβ1、TGFβ2 和血小板衍生生长因子 (PDGF)，穿透有缺陷或缺失的上皮屏障功能 (EBF) 和上皮基底膜 (EBM) 和/或 Descemet 基底膜 (DBM)，驱动角膜成纤维细胞和成纤维细胞分化为α-平滑肌肌动蛋白 (SMA)-阳性肌成纤维细胞。如果 EBF、EBM 和/或 DBM 及时得到修复或替代，通常在数周内，那么角膜成纤维细胞和成纤维细胞后代，由于缺乏必需水平的 TGFβ1 和 TGFβ2，会发生凋亡或恢复为其前体细胞类型。如果 EBF、EBM 和/或 DBM 未得到修复或替代，基质中 TGFβ1 和 TGFβ2 的水平仍然升高，并且成熟的肌成纤维细胞由角膜成纤维细胞和成纤维细胞前体产生，这些细胞产生与瘢痕纤维化相关的大量无序细胞外基质物质。这种纤维化的基质基质会持续存在，至少直到 EBF、EBM 和/或 DBM 得到再生或替代，并且角膜基质细胞去除并重组受影响的基质基质。
