Leucine-rich α-2-glycoprotein-1 promotes diabetic corneal epithelial wound healing and nerve regeneration via regulation of matrix metalloproteinases
Leucine-rich α-2-glycoprotein-1 promotes diabetic corneal epithelial wound healing and nerve regeneration via regulation of matrix metalloproteinases
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富含亮氨酸的 α-2-糖蛋白-1 通过调节基质金属蛋白酶促进糖尿病角膜上皮伤口愈合和神经再生
DOI：
10.1016/j.exer.2020.108060
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发表时间：
2020-07-01
影响因子：
3.4
通讯作者：
Xie, Lixin
中科院分区：
文献类型：
--
作者：
Li, Weina;Wang, Xiaochuan;Xie, Lixin
富含亮氨酸的α-2-糖蛋白-1(LRG1)参与多种病理生理过程，包括血管生成、皮肤创伤修复和肿瘤转移。在这项研究中，我们研究了LRG1在链脲佐菌素诱导的糖尿病小鼠角膜上皮化和神经再生中的潜在作用和机制。我们发现，与正常对照组相比，糖尿病小鼠伤后角膜上皮中LRG1的水平降低。体内和体外培养的小鼠角膜上皮干/祖细胞系(TKE2细胞)暴露于高糖(HG；30 mM)后，高血糖均可下调LRG1的表达。外源性应用LRG1可加速正常小鼠和糖尿病小鼠的角膜再上皮化和神经再生。LRG1还克服了HG条件对TKE2细胞创伤愈合的抑制作用，并通过JAK2/STAT3、AKT、表皮生长因子受体(EGFR)和转化生长因子(TGF)-β3激活了修复相关信号。我们还发现LRG1治疗克服了高血糖抑制的再生角膜上皮中基质金属蛋白酶3(MMP3)和金属蛋白酶13(MMP13)的表达。LRG1对角膜再上皮化和神经再生的促进作用可被MMP3和MMP13的抑制剂阻断。结膜下注射0.5mgMMPI对角膜上皮细胞无明显毒性损伤。免疫沉淀和邻近连接实验证实内源性LRG1在TKE2细胞中与MMP3和MMP13共沉淀。这些结果表明LRG1通过调节基质金属蛋白酶促进糖尿病角膜上皮损伤修复和神经再生。我们的发现揭示了LRG1在角膜中的新功能和新机制，并为更好地理解糖尿病角膜病变提供了新的见解。
Leucine-rich alpha-2-glycoprotein-1 (LRG1) is involved in several pathophysiological processes, including angiogenesis, cutaneous wound repair and cancer metastasis. In this study, we investigated the potential role and mechanism of LRG1 in corneal re-epithelialisation and nerve regeneration in streptozotocin-induced diabetic mice. We found decreased levels of LRG1 in the corneal epithelium after wounding in diabetic mice compared to normal controls. Hyperglycaemia downregulated the LRG1 expression in the corneal epithelium in vivo, as well as in vitro in a cultured mouse corneal epithelial stem/progenitor cell line (TKE2 cells) exposed to high glucose (HG; 30 mM) in the culture medium. Exogenous application of LRG1 accelerated corneal re-epithelialisation and nerve regeneration in normal mice and diabetic mice. LRG1 also overcame the suppression of wound healing in TKE2 cells by HG conditions, and it activated repair-related signalling by JAK2/STAT3, AKT, epidermal growth factor receptor (EGFR) and transforming growth factor (TGF)-beta 3. We also found that LRG1 treatment overcame the hyperglycaemia-suppressed expression of matrix metalloproteinase 3 (MMP3) and metalloproteinase 13 (MMP13) in the regenerated corneal epithelium. The promoted effects of LRG1 on corneal re-epithelialisation and nerve regeneration were blocked by inhibitors of MMP3 and MMP13. Subconjunctival injection of 0.5 mu g MMP inhibitors did not cause any obvious toxic damage in corneal epithelial cells. Immunoprecipitation and proximity ligation assay experiments confirmed that endogenous LRG1 coprecipitated with MMP3 and MMP13 in TKE2 cells. These results indicate that LRG1 promoted wound repair and nerve regeneration in the diabetic corneal epithelium by regulation of MMPs. Our findings reveal a new function and mechanism for LRG1 in the cornea, and they provide new insights for a better understanding of diabetic keratopathy.