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- Title
Inositol-Requiring Enzyme 1 Facilitates Diabetic Wound Healing Through Modulating MicroRNAs.
- Authors
Jie-Mei Wang; Yining Qiu; Zeng-quan Yang; Li Li; Kezhong Zhang; Wang, Jie-Mei; Qiu, Yining; Yang, Zeng-Quan; Li, Li; Zhang, Kezhong
- 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.
- Subjects
PEOPLE with diabetes; INOSITOL; WOUND healing; MICRORNA; ANGIOPOIETIN-1; NEOVASCULARIZATION; WOUNDS &; injuries; TREATMENT of diabetes; PROTEIN metabolism; ANIMALS; CELLULAR therapy; DIABETES; ELECTROPHORESIS; MEMBRANE proteins; MICE; PHOSPHORYLATION; POLYMERASE chain reaction; PROTEINS; RESEARCH funding; RNA; TRANSFERASES; WESTERN immunoblotting
- Publication
Diabetes, 2017, Vol 66, Issue 1, p177
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db16-0052