Type 2 Diabetes Restricts Multipotency of Mesenchymal Stem Cells and Impairs Their Capacity to Augment Postischemic Neovascularization in db/db Mice

Abstract

BackgroundThis 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.Methods and ResultsTo 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.ConclusionsType 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.

Type 2 Diabetes Dysregulates Glucose Metabolism in Cardiac Progenitor Cells

“…This is consistent with previous studies showing that hyperglycemia can promote adipogenic differentiation of muscle-derived stem cells (27). Interestingly, cardiac-derived cells with a mesenchymal phenotype are capable of differentiating into an adipocyte lineage in vivo (22,93), and fibroadiposis has been suggested to be a disease of CPCs "gone awry" that occurs when they differentiate into adipocytes (94). With respect to diabetes, hyperglycemia has been shown to decrease the activity of GAPDH, which metabolizes GAP to 3-phosphoglycerate.…”

“…Although it is unlikely that differentiation of CPCs contributes directly to myocardial regeneration, differentiation of stem cells has been suggested to reflect their capacity to invoke reparative responses in injured tissue (22,45). Therefore, we next examined gene programs that might indirectly regulate their restitutive actions during cell therapy.…”

Mesenchymal stromal (stem) cells to improve solid organ transplant outcome

“…of MSC donor and/or recipient may negatively affect efficacy and potency of the cellular products (52), and whether these effects can be reverted under the appropriate conditions ( i.e ., in vitro culture and/or in vivo treatments)(53-57). …”

Bone marrow mononuclear cell angiogenic competency is suppressed by a high-salt diet

“…BM-MNCs are also capable of increasing angiogenesis with critical limb ischemia in humans (54). However, several studies have now shown that the effectiveness of BM-MNC transplantation can depend on the health of the donor with demonstration of BM-MNC dysfunction observed in cardiovascular disease (57), heart failure (26), and type 2 diabetes (16,58).…”