title: Hyperglycemia inhibits cardiac stem cell-mediated cardiac repair and angiogenic capacity.
abstract: BACKGROUND
  The impact of diabetes mellitus on the cardiac regenerative potential of cardiac stem cells (CSCs) is unknown yet critical, given that individuals with diabetes mellitus may well require CSC therapy in the future. Using human and murine CSCs from diabetic cardiac tissue, we tested the hypothesis that hyperglycemic conditions impair CSC function.
  
  
  RESULTS
  CSCs cultured from the cardiac biopsies of patients with diabetes mellitus (hemoglobin A1c, 10±2%) demonstrated reduced overall cell numbers compared with nondiabetic sourced biopsies (P=0.04). When injected into the infarct border zone of immunodeficient mice 1 week after myocardial infarction, CSCs from patients with diabetes mellitus demonstrated reduced cardiac repair compared with nondiabetic patients. Conditioned medium from CSCs of patients with diabetes mellitus displayed a reduced ability to promote in vitro blood vessel formation (P=0.02). Similarly, conditioned medium from CSCs cultured from the cardiac biopsies of streptozotocin-induced diabetic mice displayed impaired angiogenic capacity (P=0.0008). Somatic gene transfer of the methylglyoxal detoxification enzyme, glyoxalase-1, restored the angiogenic capacity of diabetic CSCs (diabetic transgenic versus nondiabetic transgenic; P=0.8). Culture of nondiabetic murine cardiac biopsies under high (25 mmol/L) glucose conditions reduced CSC yield (P=0.003), impaired angiogenic (P=0.02) and chemotactic (P=0.003) response, and reduced CSC-mediated cardiac repair (P<0.05).
  
  
  CONCLUSIONS
  Diabetes mellitus reduces the ability of CSCs to repair injured myocardium. Both diabetes mellitus and preconditioning CSCs in high glucose attenuated the proangiogenic capacity of CSCs. Increased expression of glyoxalase-1 restored the proangiogenic capacity of diabetic CSCs, suggesting a means of reversing diabetic CSC dysfunction by interfering with the accumulation of reactive dicarbonyls.
authors.affiliation: From the University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors.forename: André S D
authors.initials: AS
authors.lastname: Molgat
authors.affiliation: From the University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors.forename: Everad L
authors.initials: EL
authors.lastname: Tilokee
authors.affiliation: From the University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Rafatian
authors.affiliation: From the University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors.forename: Branka
authors.initials: B
authors.lastname: Vulesevic
authors.affiliation: From the University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Ruel
authors.affiliation: From the University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors.forename: Ross
authors.initials: R
authors.lastname: Milne
authors.affiliation: From the University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Suuronen
authors.affiliation: From the University of Ottawa Heart Institute, Ottawa, Ontario, Canada. ddavis@ottawaheart.ca.
authors.forename: Darryl R
authors.initials: DR
authors.lastname: Davis
mesh_terms: D053687:Adult Stem Cells / Q000187:drug effects / Q000637:transplantation*; D000818:Animals; D017209:Apoptosis; D001706:Biopsy; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D003920:Diabetes Mellitus / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000473:pathology; D017930:Genes, Reporter; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology*; D007791:Lactoylglutathione Lyase / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D039902:Multipotent Stem Cells / Q000187:drug effects / Q000637:transplantation*; D009206:Myocardium / Q000473:pathology; D018919:Neovascularization, Physiologic; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D007791:Lactoylglutathione Lyase
keywords: adult stem cells; diabetes mellitus; myocardial infarction; oxidative stress; regeneration; stem cells