Involvement of miRNA203 in the proliferation of epidermal stem cells during the process of DM chronic wound healing through Wnt signal pathways
Involvement of miRNA203 in the proliferation of epidermal stem cells during the process of DM chronic wound healing through Wnt signal pathways
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miRNA203通过Wnt信号通路参与DM慢性伤口愈合过程中表皮干细胞增殖
DOI：
10.1186/s13287-020-01829-x
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发表时间：
2020-08-12
影响因子：
7.5
通讯作者：
Xie, Julin
中科院分区：
文献类型：
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作者：
Liu, Jian;Shu, Bin;Xie, Julin
背景miR-203在糖尿病慢性创面愈合过程中的生物学作用及其对表皮干细胞（epidermal stem cells，ESCs）增殖的影响机制尚未见报道。我们前期的研究发现，糖尿病大鼠皮肤创面中miR-203表达明显上调，ESC增殖能力受损。检测miR-203的表达水平以及ESCs数量和功能的变化。从胎鼠背部皮肤分离ESC以评估葡萄糖在体外的作用。使用针对miR-203的miR-203引物来评估其对ESC的作用。利用基因芯片技术，进一步鉴定miR-203的靶基因和信号通路。结果高糖显著上调miR-203的表达，降低ESCs的数量，抑制其增殖能力。同时，过表达miR-203可通过下调Notch和Wnt信号通路，减少ESCs的数量，降低ESCs的增殖能力。相反，miR-203的抑制增强了增殖能力。此外，沉默2型糖尿病大鼠皮肤中的miR-203通过上调Notch和Wnt信号通路加速伤口愈合并改善愈合质量。结论高糖诱导miR-203的表达，可通过下调Notch和Wnt信号通路相关基因的表达，减少2型糖尿病大鼠胚胎干细胞的数量，降低胚胎干细胞的增殖能力，导致伤口愈合延迟。
BackgroundThe 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.MethodsWound 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.ResultsWe 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.ConclusionOur 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.