| First Author | Wang JM | Year | 2017 |
| Journal | Diabetes | Volume | 66 |
| Issue | 1 | Pages | 177-192 |
| PubMed ID | 27634225 | Mgi Jnum | J:246478 |
| Mgi Id | MGI:5922687 | Doi | 10.2337/db16-0052 |
| Citation | Wang JM, et al. (2017) Inositol-Requiring Enzyme 1 Facilitates Diabetic Wound Healing Through Modulating MicroRNAs. Diabetes 66(1):177-192 |
| abstractText | 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 (IRE1alpha) 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, IRE1alpha protein expression and phosphorylation were repressed. The impaired diabetic BMPC angiogenic function was rescued by adenovirus-mediated expression of IRE1alpha but not by the RNase-inactive IRE1alpha or the activated X-box binding protein 1 (XBP1), the canonical IRE1alpha target. In fact, IRE1alpha RNase processes a subset of microRNAs (miRs), including miR-466 and miR-200 families, through which IRE1alpha plays an important role in maintaining BMPC function under the diabetic condition. IRE1alpha attenuated maturation of miR-466 and miR-200 family members at precursor miR levels through the regulated IRE1alpha-dependent decay (RIDD) independent of XBP1. IRE1alpha 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 IRE1alpha-expressing BMPCs or direct IRE1alpha 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. |
