Transplantation of MHC Homozygous Vascular Progenitors in Primates

灵长类 MHC 纯合血管祖细胞移植

• 批准号: 10181017
• 负责人: Igor I. Slukvin
• 金额: $ 115.49万
• 依托单位: MORGRIDGE INSTITUTE FOR RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-20 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10181017
• 关键词: Alleles; Animal Model; Animals; Architecture; Arteries; Biomanufacturing; Biomedical Engineering; Bioreactors; Blood Vessels; Caliber; Cardiovascular system; Cell Differentiation process; Cell Line; Cell Transplantation; Cells; Clinical; Clinical Trials; Collateral Circulation; Cyclic GMP; Documentation; Endothelial Cells; Endothelium; Engineering; Environment; Event; Goals; Heart Diseases; Human; Immune response; Immune system; Immunologic Tests; Immunologics; Individual; Investigational Drugs; Investigational New Drug Application; Macaca fascicularis; Maps; Mesenchymal; Modeling; Molecular; Monkeys; Muscle satellite cell; Patients; Peripheral Vascular Diseases; Pluripotent Stem Cells; Population; Primates; Regulator Genes; Research; Robotics; Rodent; Smooth Muscle; Smooth Muscle Myocytes; Specific qualifier value; Testing; Time; Tissue Engineering; Tissue Transplantation; Transplantation; Universities; Wisconsin; animal efficacy; cGMP production; clinically relevant; combinatorial; cost; critical limb Ischemia; design; efficacy study; in vivo; induced pluripotent stem cell; limb ischemia; manufacturing facility; pre-clinical; progenitor; radial artery; recruit; safety study; scaffold; stem cells; tissue support frame; transplant model

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.

“灵长类动物MHC纯合血管祖细胞移植”项目摘要/摘要