title: Inositol-Requiring Enzyme 1 Facilitates Diabetic Wound Healing Through Modulating MicroRNAs.
abstract: Diabetic skin ulcers represent a challenging clinical problem with mechanisms not fully understood. In this study, we investigated the role and mechanism for the primary unfolded protein response (UPR) transducer inositol-requiring enzyme 1 (IRE1α) in diabetic wound healing. Bone marrow-derived progenitor cells (BMPCs) were isolated from adult male type 2 diabetic and their littermate control mice. In diabetic BMPCs, IRE1α protein expression and phosphorylation were repressed. The impaired diabetic BMPC angiogenic function was rescued by adenovirus-mediated expression of IRE1α but not by the RNase-inactive IRE1α or the activated X-box binding protein 1 (XBP1), the canonical IRE1α target. In fact, IRE1α RNase processes a subset of microRNAs (miRs), including miR-466 and miR-200 families, through which IRE1α plays an important role in maintaining BMPC function under the diabetic condition. IRE1α attenuated maturation of miR-466 and miR-200 family members at precursor miR levels through the regulated IRE1α-dependent decay (RIDD) independent of XBP1. IRE1α deficiency in diabetes resulted in a burst of functional miRs from miR-466 and miR-200 families, which directly target and repress the mRNA encoding the angiogenic factor angiopoietin 1 (ANGPT1), leading to decreased ANGPT1 expression and disrupted angiogenesis. Importantly, cell therapies using IRE1α-expressing BMPCs or direct IRE1α gene transfer significantly accelerated cutaneous wound healing in diabetic mice through facilitating angiogenesis. In conclusion, our studies revealed a novel mechanistic basis for rescuing angiogenesis and tissue repair in diabetic wound treatments.
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI jiemei.wang@wayne.edu kzhang@med.wayne.edu.|Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI.
authors.forename: Jie-Mei
authors.initials: JM
authors.lastname: Wang
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI.
authors.forename: Yining
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, MI.
authors.forename: Zeng-Quan
authors.initials: ZQ
authors.lastname: Yang
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI.|Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI jiemei.wang@wayne.edu kzhang@med.wayne.edu.|Karmanos Cancer Institute, Wayne State University, Detroit, MI.|Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI.
authors.forename: Kezhong
authors.initials: K
authors.lastname: Zhang
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D064987:Cell- and Tissue-Based Therapy; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D014945:Wound Healing / Q000235:genetics / Q000502:physiology; D000071717:X-Box Binding Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D042683:Angiopoietin-1; C467628:Angpt1 protein, mouse; D008565:Membrane Proteins; D035683:MicroRNAs; C543719:Mirn200 microRNA, mouse; C576133:Mirn466 microRNA, mouse; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; C486556:Ern2 protein, mouse; D017346:Protein Serine-Threonine Kinases