Development of HLA engineered universal vascular grafts from human iPSCs

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Access to readily available small diameter (2-4 mm) vascular grafts presents an unmet need to patients following peripheral arterial injury or peripheral arterial atherosclerosis. Although prosthetic or autologous grafts could be utilized for this purpose, the potential risk of infection or thrombus formation in prosthetic grafts and the limited autologous vessel availability in a subset of patients arising from disease, prior utilization, or size mismatch to the injured vessel restricts their application. Acellular tissue engineered vascular grafts (TEVGs) derived from human induced pluripotent stem cells (hiPSCs) provide a promising alternative to autologous or synthetic grafts. These hiPSC-TEVGs can be constructed from vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) derived from hiPSCs and have previously been shown to have mechanical properties comparable to native vessels used in clinical bypass surgeries. hiPSC-TEVGs offer several advantages over other vascular grafts, notably the ability for hiPSCs to self-renew and differentiate into almost every cell type in the body allows for a replenishable source from which to derive VSMCs to reproducibly create TEVGs. Critically, hiPSC-TEVGs could be utilized to address the unmet needs of readily available small diameter vascular grafts for peripheral arterial injury or atherosclerosis through decellularization followed by endothelialization of the TEVG. Whereas acellular TEVGs could directly be implemented as larger diameter vascular grafts, small diameter grafts require an endothelium to prevent thrombosis in the vessel. This fact further increases the value of the hiPSC technology due to the successful derivation of hypoimmunogenic, “universal” ECs for this purpose. Hypoimmunogenic hiPSCs are created through modulating the expression of human leukocyte antigens (HLAs) so as to avoid destruction by the host immune system, while providing a healthy endothelium to small diameter grafts. Creation and investigation of the biomaterial and cellular interactions of mechanically robust, hypoimmunogenic, endothelialized hiPSC-TEVGs forms the basis of this proposal, and success here will increase the economic and practical impact of the product through enhancing short term storage capability and reaching an expansive patient populace. In pursuit of this, expansive validation and characterization will be done on hypoimmunogenic, universal EC differentiation to produce functionally and mechanically robust ECs for graft engineering. Decellularized, hypoimmunogenic endothelialized hiPSC-TEVGs will also be generated and biocompatibility of platelet- and whole blood-luminal surface interactions will be assessed. Further, in vivo immunocompatibility and therapeutic efficacy of universal hiPSC-TEVGs will be evaluated in a humanized rat aortic interposition graft model. Information gleaned from this proposal will demonstrate the diversity and practicality of the universal hiPSC-TEVG technology, and pave the way for future non-human primate, and ultimately clinical utilization of these grafts for patients with peripheral arterial injury or atherosclerosis.