The biological role of miR-203 and the underlying mechanisms on the proliferation of epidermal stem cells (ESCs) have not yet been reported during the progression of chronic wound healing in diabetes mellitus. Our previous studies have observed that the expression of miR-203 showed a marked upregulation and ESC proliferation capacity was impaired in diabetes mellitus skin wounds in rats. Wound models were established in normal rats and rats with type 2 diabetes. Expression level of miR-203 and the alteration of ESCs’ number and function were detected. ESCs were isolated from the back skin of fetal rats to assess the effects of glucose in vitro. An antagomir to miR-203 was used to assess its effect on ESCs. Using microarray analysis, we further identified potential target genes and signaling pathways of miR-203. We found that high glucose significantly upregulated the expression of miR-203 and subsequently reduced the number of ESCs and impaired their proliferation capacity. Meanwhile, over-expression of miR-203 reduced the ESCs’ numbers and impaired the proliferation capacity via downregulation of the Notch and Wnt signaling pathways. Conversely, inhibition of miR-203 enhanced the proliferation capacity. Additionally, silencing miR-203 in skin of rats with type 2 diabetes accelerated wound healing and improved healing quality via the upregulation of the Notch and Wnt signaling pathways. Finally, over-expression of miR-203 downregulated genes ROCK2, MAPK8, MAPK9, and PRKCA. Our findings demonstrated that induced expression of miR-203 by high glucose in type 2 diabetic rats decreased the number of ESCs and impaired ESC proliferation capacity via downregulating genes related to Notch and Wnt signaling pathways, resulting in a delayed wound healing.

中文翻译：

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通过Wnt信号通路在DM慢性伤口愈合过程中，miRNA203参与表皮干细胞的增殖。

在糖尿病的慢性伤口愈合过程中，尚未报道miR-203的生物学作用和表皮干细胞（ESC）增殖的潜在机制。我们以前的研究已经观察到，miR-203的表达在大鼠糖尿病皮肤伤口中显示出明显的上调，​​而ESC的增殖能力受损。在正常大鼠和2型糖尿病大鼠中建立伤口模型。检测miR-203的表达水平以及ESC数目和功能的改变。从胎儿大鼠的背部皮肤分离出ESC，以评估葡萄糖在体外的作用。使用miR-203的antagomir评估其对ESC的作用。使用微阵列分析，我们进一步确定了潜在的靶基因和miR-203的信号通路。我们发现高葡萄糖显着上调了miR-203的表达，并随后减少了ESC的数量并削弱了它们的增殖能力。同时，miR-203的过表达减少了ESC的数目，并通过Notch和Wnt信号通路的下调来损害增殖能力。相反，抑制miR-203可增强增殖能力。此外，沉默2型糖尿病大鼠皮肤中的miR-203可以通过上调Notch和Wnt信号通路来加速伤口愈合并改善愈合质量。最后，miR-203的过表达下调了ROCK2，MAPK8，MAPK9和PRKCA的基因。