Abstract
Introduction: Vascular progenitor cells (VPCs) represent the repair and regenerative potential of vasculature. VPC function has been found severely impaired in diabetes with mechanisms not fully understood. We previously demonstrated that inositol requiring-enzyme 1α (IRE1α) activity is significantly attenuated in diabetic VPCs, contributing to impaired angiogenesis in vitro . Methylglyoxal (MGO) is one of the highly reactive species generated in hyperglycemic environment. We hypothesize that MGO scavenger glyoxalase 1 (GLO1) reverses VPC dysfunction through augmenting of IRE1α, resulting in improved diabetic wound healing. Methods and Results: VPCs were isolated and cultured from the bone marrow of adult male db/db type-2 diabetic and their healthy control db/+ mice. MGO (10μM, 24h) induced immediate and severe VPC dysfunction, including impaired tube formation (Matrigel tube formation assay) and proliferation (MTT assay), increased apoptosis (Caspase 3/7 activity), which was rescued by adenovirus-mediated GLO1 over-expression (50MOI, 48h prior to MGO exposure). IRE1α expression (by Western Blot) in VPCs was decreased upon MGO exposure, but reversed by GLO1 over-expression. IRE1α RNase activity was impaired by direct MGO modification in vitro . Cell therapies using db/db VPCs with GLO1 over-expression significantly improved diabetic wound healing in vivo (6-mm full-thickness excisional wound) through facilitating angiogenesis (detected by wound capillary density), compared with diabetic control cell therapy. Conclusions: Our data suggest that GLO1 can improve VPC function in diabetes and facilitate angiogenesis by rescuing compromised efficacy of diabetic cell therapies. This is at least partly through augmenting IRE1α expression and activity. We believe that our data will provide useful information for developing novel therapeutic approaches to rescue progenitor/stem cell-mediated angiogenesis and tissue repair in diabetes.
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