title: Type 2 diabetes restricts multipotency of mesenchymal stem cells and impairs their capacity to augment postischemic neovascularization in db/db mice.
abstract: BACKGROUND
  This study tested the hypothesis that type 2 diabetes restricts multipotency of db/db mesenchymal stem cells (MSCs), promotes their terminal differentiation into adipocytes rather than endothelial cells, thereby promotes adipocytic infiltration into ischemic muscles, and reduces their capacity to participate in postischemic neovascularization.
  
  
  RESULTS
  To test this hypothesis, we transplanted MSCs from db/db or wild-type (WT) mice into WT recipients after induction of hind limb ischemia. WT recipients of db/db MSCs demonstrated adipocyte infiltration of ischemic muscle and impaired neovascularization; WT recipients of WT MSCs showed no intramuscular adipocyte infiltration and had significantly enhanced neovascularization (P<0.05; n=6). Confocal microscopy showed that the percentage of MSCs that differentiated into an adipocyte phenotype was greater and into an endothelial cell was less in WT recipients transplanted with db/db MSCs than those transplanted with WT MSCs (P<0.05; n=6). In vitro, db/db MSCs exhibited greater oxidant stress, greater adipocyte differentiation, and less endothelial differentiation than WT MSCs, and these differences were reversed by treatment with N-acetylcysteine or Nox4 siRNA (P<0.05; n=6). Insulin increased Nox4 expression, oxidant stress, and adipocyte differentiation in WT MSCs, and these insulin-induced effects were reversed by Nox4 siRNA (P<0.05; n=6). Reversal of db/db MSC oxidant stress by in vivo pretreatment with Nox4 siRNA before transplantation reversed their impaired capacity to augment postischemic neovascularization.
  
  
  CONCLUSIONS
  Type 2 diabetes-induced oxidant stress restricts the multipotency of MSCs and impairs their capacity to increase blood flow recovery after the induction of hind-limb ischemia. Reversal of MSC oxidant stress might permit greater leverage of the therapeutic potential of MSC transplantation in the setting of diabetes.
authors: Division of Vascular and Endovascular Surgery, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors: Jinglian
authors: J
authors: Yan
authors: Guodong
authors: G
authors: Tie
authors: Shouying
authors: S
authors: Wang
authors: Katharine E
authors: KE
authors: Messina
authors: Sebastian
authors: S
authors: DiDato
authors: Sujuan
authors: S
authors: Guo
authors: Louis M
authors: LM
authors: Messina
mesh_terms: D017667:Adipocytes / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement; D003921:Diabetes Mellitus, Experimental; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D015870:Gene Expression; D006614:Hindlimb / Q000098:blood supply; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007511:Ischemia / Q000209:etiology / Q000503:physiopathology*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D039902:Multipotent Stem Cells / Q000187:drug effects / Q000502:physiology; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects; D034741:RNA, Small Interfering / Q000502:physiology
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D034741:RNA, Small Interfering; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse
keywords: Nox4; limb ischemia; mesenchymal stem cells; oxidant stress; type 2 diabetes