Ameliorating methylglyoxal-induced progenitor cell dysfunction for tissue repair in diabetes

Hainan Li, Megan O’Meara, Xiang Zhang, Kezhong Zhang, Berhane Seyoum, Zhengping Yi, Randal J. Kaufman, Terrence J. Monks, Jie Mei Wang

Research output: Contribution to journalArticle

5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1287-1302
Number of pages16
JournalDiabetes
Volume68
Issue number6
DOIs
StatePublished - Jun 1 2019

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Li, H., O’Meara, M., Zhang, X., Zhang, K., Seyoum, B., Yi, Z., Kaufman, R. J., Monks, T. J., & Wang, J. M. (2019). Ameliorating methylglyoxal-induced progenitor cell dysfunction for tissue repair in diabetes. Diabetes, 68(6), 1287-1302. https://doi.org/10.2337/db18-0933