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 ( MSC s), 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. Methods and Results: To test this hypothesis, we transplanted MSC s from db/db or wild‐type ( WT ) mice into WT recipients after induction of hind limb ischemia. WT recipients of db/db MSC s demonstrated adipocyte infiltration of ischemic muscle and impaired neovascularization; WT recipients of WT MSC s showed no intramuscular adipocyte infiltration and had significantly enhanced neovascularization ( P db/db MSC s than those transplanted with WT MSC s ( P db/db MSC s exhibited greater oxidant stress, greater adipocyte differentiation, and less endothelial differentiation than WT MSC s, and these differences were reversed by treatment with N ‐acetylcysteine or Nox4 siRNA ( P P 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 MSC s 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.