@article{c06f48e73e3e426aa1106d2dfc04540f,
title = "Ameliorating methylglyoxal-induced progenitor cell dysfunction for tissue repair in diabetes",
abstract = "Patient-derived progenitor cell (PC) dysfunction is severely impaired in diabetes, but the molecular triggers that contribute to mechanisms of PC dysfunction are not fully understood. Methylglyoxal (MGO) is one of the highly reactive dicarbonyl species formed during hyperglycemia. We hypothesized that the MGO scavenger glyoxalase 1 (GLO1) reverses bone marrow-derived PC (BMPC) dysfunction through augmenting the activity of an important endoplasmic reticulum stress sensor, inositol-requiring enzyme 1a (IRE1a), resulting in improved diabetic wound healing. BMPCs were isolated from adult male db/db type 2 diabetic mice and their healthy corresponding control db/+ mice. MGO at the concentration of 10 mmol/L induced immediate and severe BMPC dysfunction, including impaired network formation, migration, and proliferation and increased apoptosis, which were rescued by adenovirus-mediated GLO1 overexpression. IRE1a expression and activation in BMPCs were significantly attenuated by MGO exposure but rescued by GLO1 overexpression. MGO can diminish IRE1a RNase activity by directly binding to IRE1a in vitro. In a diabetic mouse cutaneous wound model in vivo, cell therapies using diabetic cells with GLO1 overexpression remarkably accelerated wound closure by enhancing angiogenesis compared with diabetic control cell therapy. Augmenting tissue GLO1 expression by adenovirus-mediated gene transfer or with the small-molecule inducer trans-resveratrol and hesperetin formulation also improved wound closure and angiogenesis in diabetic mice. In conclusion, our data suggest that GLO1 rescues BMPC dysfunction and facilitates wound healing in diabetic animals, at least partly through preventing MGO-induced impairment of IRE1a expression and activity. Our results provide important knowledge for the development of novel therapeutic approaches targeting MGO to improve PC-mediated angiogenesis and tissue repair in diabetes.",
author = "Hainan Li and Megan O{\textquoteright}Meara and Xiang Zhang and Kezhong Zhang and Berhane Seyoum and Zhengping Yi and Kaufman, {Randal J.} and Monks, {Terrence J.} and Wang, {Jie Mei}",
note = "Funding Information: Acknowledgments. The authors acknowledge the outstanding technical support for real-time PCR analyses provided by Dr. Fei Chen and technical assistance for BMPC isolation provided by Yihan Wang (both in the Department of Pharmaceutical Sciences at Wayne State University). The authors also thank the staff from the Department of Laboratory Animal Research at Wayne State University for providing excellent care for the animals. Funding. This work was supported in part by National Institute of Diabetes and Digestive and Kidney Diseases grants R01-DK-090313 (to K.Z.); R01-DK-107666 and R01-DK-081750 (to Z.Y.); R01-DK-103185, R24-DK-110973, and R01-DK-113171 (to R.J.K.); and R01-DK-109036 (to J.-M.W.). This work also was supported by Wayne State University Undergraduate Research and Creative Projects (to M.O.) and Wayne State University Cardiovascular Research Institute Isis Award 2017 (to J.-M.W.). R.J.K. is a member of the University of California, San Diego, Diabetes Research Center (P30 DK063491) and adjunct professor in the Department of Pharmacology, University of California, San Diego. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. H.L. conducted experiments, acquired data, analyzed data, and wrote the manuscript. M.O. conducted experiments, acquired data, and edited the manuscript. X.Z. assisted with editing the manuscript. K.Z. provided the key reagent, conceived the idea of IRE1a-mediated miR degradation, contributed to the discussion, and edited the manuscript. B.S. and Z.Y. provided clinical assistance for human sample collection, contributed to the discussion, and edited the manuscript. R.J.K. provided the key reagent and edited the manuscript. T.J.M. conceived the idea, contributed to the discussion, and edited the manuscript. J.-M.W. conceived the idea, designed the research studies, analyzed data, wrote the manuscript, and provided research funding. J.-M.W. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Data Availability. All data generated or analyzed during this study are included in the published manuscript (and Supplementary Data). The IRE1a floxed mice that support the findings of this study are available from R.J.K., but restrictions apply to the availability of these mice, which were used under license for the current study and therefore are not publicly available. IRE1a floxed mice may be available from the authors and/or R.J.K. upon reasonable request and with permission of R.J.K. Funding Information: This work was supported in part by National Institute of Diabetes and Digestive and Kidney Diseases grants R01-DK-090313 (to K.Z.); R01-DK-107666 and R01-DK-081750 (to Z.Y.); R01-DK-103185, R24-DK-110973, and R01-DK-113171 (to R.J.K.); and R01-DK-109036 (to J.-M.W.). This work also was supported by Wayne State University Undergraduate Research and Creative Projects (to M.O.) and Wayne State University Cardiovascular Research Institute Isis Award 2017 (to J.-M.W.). R.J.K. is a member of the University of California, San Diego, Diabetes Research Center (P30 DK063491) and adjunct professor in the Department of Pharmacology, University of California, San Diego. Publisher Copyright: {\textcopyright} 2019 by the American Diabetes Association.",
year = "2019",
month = jun,
day = "1",
doi = "10.2337/db18-0933",
language = "English (US)",
volume = "68",
pages = "1287--1302",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "6",
}