The goal of this project is to enhance the means to use mesenchymal stem cells (MSC) for the treatment of peripheral artery disease, particularly in the diabetic patient. MSC transplantation hold great promise as a therapeutic intervention for PAD based on their pluripotency, as well as their efficacy in paracrine delivery of proangiogenic factors. However, we have determined that diabetic MSC manifest greater oxidant stress than healthy (WT) MSC. Diabetic MSC display restricted pluripotency, favoring adipocytic over endothelial differentiation;when transplanted into a WT host, diabetic MSC impair post-ischemic neovascularization and generate fatty infiltration in the ischemic hindlimb. The project hypothesis is that oxidant stress in diabetic MSC restricts their pluripotency and hence their neovascularization capacity.
Three aims are proposed to test this hypothesis.
Specific Aim 1 will demonstrate that oxidant production is the basis for restricted pluripotency in diabetic MSC, using a reductionist approach in cultured MSC. Exp  will determine if Nox4-derived H2O2 drives adipocyte differentiation in diabetic MSC. Exp  will determine the role of PPAR3-overexpression in diabetic MSC in generating adipocyte differentiation. Exp  will determine the role of uncoupled eNOS in generating oxidant stress in diabetic MSC and evaluate strategies for eNOS recoupling. Exp  will determine if deficiencies of the VEGF-Akt-eNOS pathway are the basis for impaired endothelial differentiation in diabetic MSC.
Specific Aim 2 will use an in vivo MSC transplant paradigm to demonstrate that antioxidant treatment of diabetic MSCs or the diabetic host improves the efficacy of MSC transplant vis-a-vis post-ischemic neovascularization. Exp  will determine if ex vivo treatment of diabetic MSC with N-acetylcysteine (NAC) or other agents with direct or indirect antioxidant properties (resveratrol, rosiglitazone, rosuvastatin) improve their function upon subsequent transplant into a WT host in the setting of hindlimb ischemia. Exp  will determine if treatment of the db/db recipient mouse with NAC, or the other agents just noted, improve the outcome of MSC transplant in the setting of hindlimb ischemia.
Specific Aim 3 will demonstrate that genetic engineering of MSC to enhance their expression of proangiogenic factors improves their participation in post-ischemic neovascularization. Exp  will determine if overexpression of wild type eNOS or constitutively active Akt in MSCs prior to transplant increases eNOS activation and eNOS-derived NO production, and in turn improves their efficacy in the treatment post-ischemic neovascularization. Exp  will determine if selection MSC expressing the chemokine receptor CXCR4 increases the homing of these cells to the ischemic hindlimb. If homing is improved, then this CXCR4+ MSC will undergo genetic engineering to maximize their in vivo functional capacity.
Current treatments for peripheral artery disease (PAD) are either palliative and treatment options are particularly limited in patients with the common co-morbidity of diabetes mellitus;discovery of novel therapeutic options are an urgent matter of national health care priority. Autologous transplantation with mesenchymal stem cells (MSC), a pluripotent cell that par- ticipates in post-ischemic neovascularization, holds great promise as a means to effect symptomatic relief by reversing disease pathology. The proposed work will elucidate the mechanisms responsible for the loss of pluripotency and therapeutic efficacy of diabetic MSC, as well as greatly increase knowledge regarding the basic and applied vascular biology of MSC in the treatment of lower extremity ischemia.
|Tie, Guodong; Messina, Katharine E; Yan, Jinglian et al. (2014) Hypercholesterolemia induces oxidant stress that accelerates the ageing of hematopoietic stem cells. J Am Heart Assoc 3:e000241|
|Yan, Jinglian; Tie, Guodong; Xu, Ting Yu et al. (2013) Mesenchymal stem cells as a treatment for peripheral arterial disease: current status and potential impact of type II diabetes on their therapeutic efficacy. Stem Cell Rev 9:360-72|
|Yan, Jinglian; Tie, Guodong; Messina, Louis M (2012) Tetrahydrobiopterin, L-arginine and vitamin C actsynergistically to decrease oxidative stress, increase nitricoxide and improve blood flow after induction of hindlimbischemia in the rat. Mol Med 18:676-84|
|Yan, Jinglian; Tie, Guodong; Wang, Shouying et al. (2012) Type 2 diabetes restricts multipotency of mesenchymal stem cells and impairs their capacity to augment postischemic neovascularization in db/db mice. J Am Heart Assoc 1:e002238|
|Yan, Jinglian; Tie, Guodong; Hoffman, Ari et al. (2010) Oral tetrahydrobiopterin improves the beneficial effect of adenoviral-mediated eNOS gene transfer after induction of hindlimb ischemia. Mol Ther 18:1482-9|
|Park, Brian; Hoffman, Ari; Yang, Yagai et al. (2010) Endothelial nitric oxide synthase affects both early and late collateral arterial adaptation and blood flow recovery after induction of hind limb ischemia in mice. J Vasc Surg 51:165-73|
|Li, J M; Newburger, P E; Gounis, M J et al. (2010) Local arterial nanoparticle delivery of siRNA for NOX2 knockdown to prevent restenosis in an atherosclerotic rat model. Gene Ther 17:1279-87|
|Tie, Guodong; Yan, Jinglian; Yang, Yagai et al. (2010) Oxidized low-density lipoprotein induces apoptosis in endothelial progenitor cells by inactivating the phosphoinositide 3-kinase/Akt pathway. J Vasc Res 47:519-30|
|Sneider, Erica B; Nowicki, Philip T; Messina, Louis M (2009) Regenerative medicine in the treatment of peripheral arterial disease. J Cell Biochem 108:753-61|
|Yan, Jinglian; Tie, Guodong; Park, Brian et al. (2009) Recovery from hind limb ischemia is less effective in type 2 than in type 1 diabetic mice: roles of endothelial nitric oxide synthase and endothelial progenitor cells. J Vasc Surg 50:1412-22|
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