The Pro-fibrotic Response of Mesenchymal Leader Cells to Lens Wounding Involves Hyaluronic Acid, Its Receptor RHAMM, and Vimentin.
The Pro-fibrotic Response of Mesenchymal Leader Cells to Lens Wounding Involves Hyaluronic Acid, Its Receptor RHAMM, and Vimentin.
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DOI：
10.3389/fcell.2022.862423
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发表时间：
2022
影响因子：
5.5
通讯作者：
Walker JL
中科院分区：
文献类型：
--
作者：
Menko AS;Romisher A;Walker JL
透明质酸/透明质酸 (HA) 是伤口后细胞沉积的临时基质的主要成分，在调节细胞迁移以修复伤口和促进伤口纤维化结果方面发挥作用。两者均通过其受体 CD44 和 RHAMM 介导。我们现在表明，HA 存在于白内障术后外植体伤口模型中基质表面上组装的临时基质中，其中间充质前导细胞填充伤口边缘，以引导晶状体上皮迁移穿过组装有该基质的相邻培养基质。用 4-MU 抑制 HA 表达可阻断伤口响应性间充质前导细胞组装 FN-EDA 和 I 型胶原蛋白及其迁移。这些细胞表达 HA 受体 CD44 和 RHAMM。 CD44 与 HA 在细胞-细胞界面处共定位。 RHAMM 在由前缘的间充质细胞延伸的片状足突起中占主导地位，并且沿着在基底表面上组织的 HA 原纤维。晶状体受伤后几天内，前导细胞被诱导转变为 αSMA+ 肌成纤维细胞。由于 HA/RHAMM 与细胞迁移和诱导纤维化有关，我们检查了阻断 HA 合成对肌成纤维细胞出现的影响，发现它依赖于 HA。虽然 RHAMM 之前并未与中间丝蛋白波形蛋白联系起来，但我们对这些外植体培养物的研究表明，细胞板状足突起中的波形蛋白调节它们向肌成纤维细胞的转变。 PLA 研究现在表明，RHAMM 在前导细胞的板状突起中与 HA 和波形蛋白复合，表明这种 HA/RHAMM/波形蛋白复合物在损伤后调节前导细胞功能，促进细胞迁移和这些细胞向肌成纤维细胞的转变。这些结果增加了我们对受伤后基质环境如何与受体/细胞骨架复合物相互作用的理解，以确定损伤结果是再生还是纤维化。
Hyaluronic Acid/Hyaluronan (HA) is a major component of the provisional matrix deposited by cells post-wounding with roles both in regulating cell migration to repair a wound and in promoting a fibrotic outcome to wounding. Both are mediated through its receptors CD44 and RHAMM. We now showed that HA is present in the provisional matrix assembled on the substrate surface in a lens post-cataract surgery explant wound model in which mesenchymal leader cells populate the wound edges to direct migration of the lens epithelium across the adjacent culture substrate onto which this matrix is assembled. Inhibiting HA expression with 4-MU blocked assembly of FN-EDA and collagen I by the wound-responsive mesenchymal leader cells and their migration. These cells express both the HA receptors CD44 and RHAMM. CD44 co-localized with HA at their cell-cell interfaces. RHAMM was predominant in the lamellipodial protrusions extended by the mesenchymal cells at the leading edge, and along HA fibrils organized on the substrate surface. Within a few days post-lens wounding the leader cells are induced to transition to αSMA+ myofibroblasts. Since HA/RHAMM is implicated in both cell migration and inducing fibrosis we examined the impact of blocking HA synthesis on myofibroblast emergence and discovered that it was dependent on HA. While RHAMM has not been previously linked to the intermediate filament protein vimentin, our studies with these explant cultures have shown that vimentin in the cells’ lamellipodial protrusions regulate their transition to myofibroblast. PLA studies now revealed that RHAMM was complexed with both HA and vimentin in the lamellipodial protrusions of leader cells, implicating this HA/RHAMM/vimentin complex in the regulation of leader cell function post-wounding, both in promoting cell migration and in the transition of these cells to myofibroblasts. These results increase our understanding of how the post-wounding matrix environment interacts with receptor/cytoskeletal complexes to determine whether injury outcomes are regenerative or fibrotic.
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影响因子：
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通讯作者：
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