Project Summary/Abstract for, “Transplantation of MHC homozygous vascular progenitors in primates.” For tissue engineered arteries, the use of patient specific iPS cells would be severely limited by time constraints and cost. Banking iPS cells from rare individuals homozygous for HLA alleles has been proposed as a strategy to allow economies of scale, while still reducing rejection of iPS cell-derived transplanted tissues. Only a few hundred such cell lines would provide matches for the majority of the U.S. population, and the Waisman Clinical Biomanufacturing facility here on the University of Wisconsin has already produced cGMP HLA homozygous iPS cell lines. However, the immunological value of such an approach remains untested in an animal model with an immune system similar to the human immune system. Here we will use a unique population of MHC defined cynomolgus monkeys to test the immune response to MHC homozygous cynomolgus iPS cell-derived vascular cells transplanted to MHC haploidentical recipients. Using the MHC defined cynomolgus monkeys, we will use a limb ischemia model to determine the ability of iPS cell-derived arterial endothelial cells to contribute to collateral circulation when transplanted by themselves, in combination with iPS cell-derived smooth muscle cells, or when combined into a fully tissue engineered artery. A central premise of this proposal is that properly specified early arterial endothelial cells will robustly recruit, expand, and mature endogenous or co-transplanted smooth muscle cell progenitors to increase arteriogenesis in vivo, and that these arterial endothelial cells will be critical to producing tissue engineered arteries ex vivo that remain functional long after transplantation. The final goal of this proposal is to produce cGMP vascular progenitors from HLA homozygous human iPS cell lines for the pre-clinical animal studies required to file an IND for critical limb ischemia. With extensive human and primate pluripotent stem cell expertise, a strong bioengineering department, a National Primate Research Center with an MHC typing facility, and a GMP cell manufacturing facility, the environment at the University of Wisconsin is uniquely suited for completing the goals of this proposal.

Project Narrative, “Transplantation of MHC homozygous vascular progenitors in primates.” Vascular transplants are used routinely to treat heart disease and peripheral vascular disease, but there is often no suitable vessel available for transplantation. Here we will study how to produce vascular progenitors from induced pluripotent stem (iPS) cells, assemble them into tissue engineered arteries, and test them in a genetically defined primate that should accurately model both the human circulatory and immune systems. The proposed studies will result in the production of cGMP human vascular progenitors to support the animal efficacy and safety studies required prior to the initiation of a clinical trial for critical limb ischemia.