Diabetic skin ulcers represent a challenging clinical problem with mechanisms not fully understood. In a recent study by researchers from Wayne State University, they investigated the role and mechanism for the primary Unfolded Protein Response (UPR) transducer inositol requiring enzyme 1 (IRE1α) in diabetic wound healing.

In their study, 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 IRE1á or the activated X-box binding protein 1 (XBP1), the canonical IRE1á target. In fact, IRE1á RNase processes a subset of microRNAs (miRs), including miR-466 and miR-200 families, through which IRE1á plays an important role in maintaining BMPC function under the diabetic condition. IRE1á attenuated maturation of miR-466 and miR-200 family members at precursor miR levels through the Regulated IRE1α-Dependent Decay (RIDD) independent of XBP1. IRE1á 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, this study revealed a novel mechanistic basis for rescuing angiogenesis and tissue repair in diabetic wound treatments.

 

Heat map of miRNA microarray analysis in db/+ and db/db BMPCs. n=3 per group

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Reference

J-M. Wang, Y. Qiu, Z-Q. Yang, L. Li, K. Zhang (2016) Inositol Requiring Enzyme 1 Facilitates Diabetic Wound Healing through Modulating microRNAs Diabetes 6(10) doi: 10.2337/db16-0052 [article]