Increased Expression of EGR-1 in Diabetic Human Adipose Tissue-Derived Mesenchymal Stem Cells Reduces Their Wound Healing Capacity
Increased Expression of EGR-1 in Diabetic Human Adipose Tissue-Derived Mesenchymal Stem Cells Reduces Their Wound Healing Capacity
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DOI：
10.1089/scd.2015.0335
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发表时间：
2016-05-15
影响因子：
4
通讯作者：
Ohneda, Osamu
中科院分区：
文献类型：
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作者：
Nhu-Thuy Trinh;Yamashita, Toshiharu;Ohneda, Osamu
导致糖尿病并发症的2型糖尿病（T2DM）的患病率在全球范围内呈上升趋势。t2dm来源的干细胞在细胞治疗中的可能应用是有限的，因为它们的特性仍未完全了解。在这项研究中，我们对来自糖尿病患者的脂肪组织来源的间充质干细胞（at - mscs）进行了表征，发现胰岛素受体底物-1 （IRS-1）在dAT-MSCs中在丝氨酸636/639处高度磷酸化。此外，我们发现早期生长反应因子-1 （EGR-1）及其靶基因PTEN和GGPS1在dAT-MSCs中的表达高于健康供体来源AT-MSCs （nAT-MSCs）。我们观察了在缺血皮瓣小鼠模型中注射dAT-MSCs后伤口愈合受损。小发夹rna靶向EGR-1 （shEGR-1）和丝裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/ERK）抑制剂（PD98059）可降低EGR-1及其靶基因的表达。重要的是，在小鼠模型中，带有shEGR-1的dAT-MSCs能够恢复伤口愈合能力。有趣的是，在缺氧条件下，缺氧诱导因子-1 （HIF-1）可以在dAT-MSCs中与EGR-1启动子结合，而在nAT-MSCs中则不能。综上所述，这些结果表明，在dAT-MSCs中，EGR-1的表达上调通过两条途径进行，主要调控途径是MAPK/ERK途径，另一条途径是HIF-1通过在EGR1基因启动子区域的直接转录激活介导。我们的研究表明，dAT-MSCs可能通过过度表达EGR-1导致微血管损伤和延迟伤口愈合。阻断dAT-MSCs中EGR-1的表达可能是治疗糖尿病患者慢性伤口的有效方法。
The prevalence of type 2 diabetes mellitus (T2DM), which leads to diabetic complications, has been increasing worldwide. The possible applications of T2DM-derived stem cells in cell therapy are limited because their characteristics are still not fully understood. In this study, we characterized adipose tissue-derived mesenchymal stem cells (AT-MSCs) from diabetic patients (dAT-MSCs) and found that insulin receptor substrate-1 (IRS-1) was highly phosphorylated at serine 636/639 in dAT-MSCs. Moreover, we found that early growth response factor-1 (EGR-1) and its target genes of PTEN and GGPS1 were highly expressed in dAT-MSCs in comparison to healthy donor-derived AT-MSCs (nAT-MSCs). We observed impaired wound healing after the injection of dAT-MSCs in the ischemic flap mouse model. The expressions of EGR-1 and its target genes were diminished by small hairpin RNA-targeted EGR-1 (shEGR-1) and treatment with a mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) inhibitor (PD98059). Importantly, dAT-MSCs with shEGR-1 were able to restore the wound healing ability in the mouse model. Interestingly, under hypoxic conditions, hypoxia-inducible factor-1 (HIF-1) can bind to the EGR-1 promoter in dAT-MSCs, but not in nAT-MSCs. Together, these results demonstrate that the expression of EGR-1 was upregulated in dAT-MSCs through two pathways: the main regulatory pathway is the MAPK/ERK pathway, the other is mediated by HIF-1 through direct transcriptional activation at the promoter region of the EGR1 gene. Our study suggests that dAT-MSCs may contribute to microvascular damage and delay wound healing through the overexpression of EGR-1. Interrupting the expression of EGR-1 in dAT-MSCs may be a useful treatment for chronic wounds in diabetic patients.