Applying induced pluripotent stem cell derived endothelial cells to regenerative therapy in chronic limb threatening ischemia

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Peripheral arterial disease (PAD) is highly prevalent among the Veteran population. Veterans experience PAD onset at an earlier age than their non-Veteran counterparts and are at increased risk of experiencing adverse outcomes from peripheral arterial disease. Chronic limb threatening ischemia (CLTI), the most severe form of peripheral arterial disease, is a significant cause of morbidity, including persistent pain at rest, neuronal dysfunction, and ultimately limb loss. While endovascular and surgical treatment options have advanced, many patients are not candidates for revascularization due to anatomic constraints or co-morbidities. Therapies for these “no-option CLTI” patients are limited to palliation consisting of pain control and major amputation, both of which lead to significant morbidity and disability. Improved therapeutic modalities to treat this “no-option CLTI” population and to prevent limb loss are desperately needed. Stem cell-based therapies have emerged as a promising new modality to treat this “no-option CLTI” population. The advent of induced pluripotent stem cell (iPSC) technology allows for an infinitely reproducible and scalable source of stem cells. This technology was rendered applicable to vascular disease by the establishment of reliable directed differentiation of said stem cells to the myriad vascular cell types required for a functional blood vessel. Our prior work overcame the barrier of premature loss of EC function and replicative senescence in culture, opening the door to the next steps in developing iPSC-EC therapeutics. This proposal aims to (1) validate the survival and function of clinical grade iPSC-ECs in implantable and resorbable platelet lysate hydrogels, and (2) quantify the restoration of limb perfusion and function after implantation of hydrogels containing iPSC-ECs into ischemic mouse hindlimbs. This work will generate a critical pre-clinical animal model of utilizing PAD patient-derived iPSC-ECs to promote local vascular regeneration in ischemic limbs as a novel therapy for CLTI.