title: Increased Expression of EGR-1 in Diabetic Human Adipose Tissue-Derived Mesenchymal Stem Cells Reduces Their Wound Healing Capacity.
abstract: 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-1α (HIF-1α) 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-1α 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.
authors.affiliation: 1 Graduate School of Comprehensive Human Science, Laboratory of Regenerative Medicine and Stem Cell Biology, University of Tsukuba , Tsukuba, Japan .
authors.forename: Nhu-Thuy
authors.initials: NT
authors.lastname: Trinh
authors.affiliation: 1 Graduate School of Comprehensive Human Science, Laboratory of Regenerative Medicine and Stem Cell Biology, University of Tsukuba , Tsukuba, Japan .
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: 2 Laboratory of Molecular Pathophysiology, Faculty of Pharmacy, Takasaki University of Health and Welfare , Takasaki, Japan .
authors.forename: Kinuko
authors.initials: K
authors.lastname: Ohneda
authors.affiliation: 1 Graduate School of Comprehensive Human Science, Laboratory of Regenerative Medicine and Stem Cell Biology, University of Tsukuba , Tsukuba, Japan .
authors.forename: Kenichi
authors.initials: K
authors.lastname: Kimura
authors.affiliation: 1 Graduate School of Comprehensive Human Science, Laboratory of Regenerative Medicine and Stem Cell Biology, University of Tsukuba , Tsukuba, Japan .
authors.forename: Georgina To'a
authors.initials: GT
authors.lastname: Salazar
authors.affiliation: 3 Department of Cardiovascular Surgery, University of Tsukuba , Tsukuba, Japan .
authors.forename: Fujio
authors.initials: F
authors.lastname: Sato
authors.affiliation: 1 Graduate School of Comprehensive Human Science, Laboratory of Regenerative Medicine and Stem Cell Biology, University of Tsukuba , Tsukuba, Japan .
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohneda
mesh_terms: D000273:Adipose Tissue / Q000473:pathology*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D002462:Cell Membrane / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology*; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D012867:Skin / Q000473:pathology; D013524:Surgical Flaps; D014945:Wound Healing
chemical_list: D015415:Biomarkers; D051766:Early Growth Response Protein 1; D048049:Extracellular Signal-Regulated MAP Kinases