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Leucine-rich α-2-glycoprotein-1 promotes diabetic corneal epithelial wound healing and nerve regeneration via regulation of matrix metalloproteinases.
Experimental Eye Research ( IF 3.4 ) Pub Date : 2020-05-06 , DOI: 10.1016/j.exer.2020.108060
Weina Li 1 , Xiaochuan Wang 2 , Jun Cheng 3 , Jing Li 2 , Qun Wang 3 , Qingjun Zhou 3 , Hua Li 3 , Junfa Xue 3 , Yuan Zhang 1 , Lingling Yang 3 , Lixin Xie 1
Affiliation  

Leucine-rich α-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)-β3. 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 μg 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.

中文翻译:

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的愈合和神经再生。

富含亮氨酸的α-2-糖蛋白-1(LRG1)参与多个病理生理过程,包括血管生成,皮肤伤口修复和癌症转移。在这项研究中,我们调查了LRG1在链脲佐菌素诱导的糖尿病小鼠角膜上皮再形成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,糖尿病小鼠受伤后角膜上皮中LRG1的水平降低。高血糖症在体内以及暴露于培养基中暴露于高葡萄糖(HG; 30 mM)的培养的小鼠角膜上皮干/祖细胞系(TKE2细胞)中都下调了角膜上皮中LRG1的表达。在正常小鼠和糖尿病小鼠中,外源应用LRG1可以加速角膜再上皮形成和神经再生。LRG1还克服了HG条件对TKE2细胞伤口愈合的抑制作用,它通过JAK2 / STAT3,AKT,表皮生长因子受体(EGFR)和转化生长因子(TGF)-β3激活了修复相关的信号传导。我们还发现LRG1治疗克服了再生角膜上皮中高血糖素抑制的基质金属蛋白酶3(MMP3)和金属蛋白酶13(MMP13)的表达。LRG1对角膜上皮再形成和神经再生的促进作用被MMP3和MMP13抑制剂阻断。结膜下注射0.5μgMMP抑制剂不会对角膜上皮细胞造成任何明显的毒性损害。免疫沉淀和邻近连接测定实验证实,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MMPs促进了糖尿病角膜上皮的伤口修复和神经再生。我们的发现揭示了LRG1在角膜中的新功能和机制,它们为更好地了解糖尿病性角膜病提供了新的见解。
更新日期:2020-05-06
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