Treatment of diabetic limb ischemia with human induced pluripotent stem cells
Diabetes is a rapidly growing global health problem. Patients with diabetes are frequently affected by vascular complications such as coronary artery disease and peripheral arterial disease (PAD). PAD is usually characterized by occlusive arterial disease of the lower extremities, and when advanced into the critical limb ischemia stage can lead to leg amputation. As advanced PAD in diabetes frequently affects small vessels, conventional percutaneous intervention and surgical treatment are ineffective in a number of cases. Although recent biological revascularization strategies using cell therapy with bone marrow (BM) or peripheral blood derived mononuclear cells or endothelial progenitor cells (EPCs) have been attempted for growing blood vessels (therapeutic neovascularization), the effects are at best marginal. Recently, a series of studies reported that reprogramming of fully differentiated mouse and human somatic cells into undifferentiated, pluripotent stem cells could be achieved by introducing pluripotency-related transcription factors (OCT4, SOX2. c-MYC, KLF-4, NANOG, LIN28). These induced pluripotent stem cells (iPSCs) closely resemble embryonic stem cells (ESCs). Therefore, it is anticipated that directly differentiated iPSCs could be used for tissue regeneration in diabetic patients. Since the main pathogenetic deficit in PAD is the endothelial cells (ECs), generation of ECs or their progenitor cells is crucial to developing effective therapies. We have recently generated human iPSCs (hiPSCs) from human somatic cells. Moreover, we have established a novel culture system to differentiate these hiPSCs into ECs, and have confirmed their in vivo vasculogenic activities. Despite the critical need for ECs for treating ischemic vascular disease, to date, no studies have addressed the therapeutic potential of ECs differentiated from hiPSCs. In this proposal we will determine the therapeutic and revascularization effects of hiPSC-derived ECs (hiPS-ECs) on experimental hindlimb ischemia in diabetic animals. We anticipate that this study will yield novel insight into the role of endothelially differentiated hiPSCs in regenerating vasculature and/or treating ischemic vascular disease in diabetic patients.

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