Sustained Release of TPCA-1 from Silk Fibroin Hydrogels Preserves Keratocyte Phenotype and Promotes Corneal Regeneration by Inhibiting Interleukin-1β Signaling
Sustained Release of TPCA-1 from Silk Fibroin Hydrogels Preserves Keratocyte Phenotype and Promotes Corneal Regeneration by Inhibiting Interleukin-1β Signaling
复制标题
丝素蛋白水凝胶中持续释放 TPCA-1 通过抑制 Interleukin-1 beta 信号传导保留角质细胞表型并促进角膜再生
DOI：
10.1002/adhm.202000591
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发表时间：
2020-08-02
影响因子：
10
通讯作者：
Danielson, Patrik
中科院分区：
文献类型：
--
作者：
Zhang, Wei;Chen, Jialin;Danielson, Patrik
眼外伤或感染引起的角膜损伤是现有的最具挑战性的视力损害病理之一。许多研究重点关注白介素 1 β (IL-1 β) 对角膜伤口愈合的促炎和促血管生成作用。然而，IL-1β对角膜细胞表型和角膜修复的影响以及潜在机制尚不清楚。这项研究首次报道，IL-1 beta 通过显着下调角膜细胞标志物（Keratocan、Lumican、Aldh3a1 和 CD34）的基因和蛋白质表达水平，在体外诱导角膜细胞表型变化。此外，研究发现NF-kappa B通路参与IL-1β诱导的角膜细胞表型变化，并且抑制NF-kappa B的选择性IKKβ抑制剂TPCA-1可以在体外IL-1β模拟病理条件下保留角膜细胞表型。通过使用角膜损伤的小鼠模型，结果表明，可降解丝素蛋白水凝胶持续释放TPCA-1可加速角膜伤口愈合，改善角膜透明度，增强角膜细胞标记物的表达，并支持组织良好的上皮和基质的再生。这些发现不仅为角膜伤口愈合的病理生理机制提供了见解，而且还为角膜损伤患者新疗法的潜在开发提供了见解。
Corneal injury due to ocular trauma or infection is one of the most challenging vision impairing pathologies that exists. Many studies focus on the pro-inflammatory and pro-angiogenic effects of interleukin-1 beta(IL-1 beta) on corneal wound healing. However, the effect of IL-1 beta on keratocyte phenotype and corneal repair, as well as the underlying mechanisms, is not clear. This study reports, for the first time, that IL-1 beta induces phenotype changes of keratocytes in vitro, by significantly down-regulating the gene and protein expression levels of keratocyte markers (Keratocan, Lumican, Aldh3a1 and CD34). Furthermore, it is found that the NF-kappa B pathway is involved in the IL-1 beta-induced changes of keratocyte phenotype, and that the selective IKK beta inhibitor TPCA-1, which inhibits NF-kappa B, can preserve keratocyte phenotype under IL-1 beta simulated pathological conditions in vitro. By using a murine model of corneal injury, it is shown that sustained release of TPCA-1 from degradable silk fibroin hydrogels accelerates corneal wound healing, improves corneal transparency, enhances the expression of keratocyte markers, and supports the regeneration of well-organized epithelium and stroma. These findings provide insights not only into the pathophysiological mechanisms of corneal wound healing, but also into the potential development of new treatments for patients with corneal injuries.