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Transplantation of MHC Homozygous Vascular Progenitors in Primates

灵长类 MHC 纯合血管祖细胞移植

基本信息

批准号：
9215301
负责人：
James Alexander Thomson
金额：
$ 90.36万
依托单位：
MORGRIDGE INSTITUTE FOR RESEARCH, INC.
依托单位国家：
美国
项目类别：
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/9215301
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 Cell Transplants Cells Clinical Clinical Trials Collateral Circulation Cyclic GMP Documentation Endothelial Cells Engineering Environment Event Goals Heart Diseases Human Immune response Immune system Individual Investigational Drugs Investigational New Drug Application Ischemia Limb structure Macaca fascicularis Maps Mesenchymal Modeling Molecular Monkeys Patients Peripheral Vascular Diseases Pluripotent Stem Cells Population Primates Recruitment Activity Regulator Genes Research Robotics Rodent Smooth Muscle Smooth Muscle Myocytes Specific qualifier value Stem cells Testing Time Tissue Engineering Transplantation Transplanted tissue Universities Wisconsin abstracting animal efficacy cGMP production clinically relevant combinatorial cost design in vivo induced pluripotent stem cell manufacturing facility pre-clinical progenitor radial artery safety study scaffold

项目摘要

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.

项目摘要/摘要，“灵长类动物 MHC 纯合血管祖细胞的移植”。对于组织工程动脉，患者特异性 iPS 细胞的使用将受到时间的严重限制限制和成本。已提议从 HLA 等位基因纯合的稀有个体中储存 iPS 细胞作为一种实现规模经济的策略，同时仍然减少对 iPS 细胞衍生的移植组织的排斥。只有几百个这样的细胞系才能为大多数美国人提供匹配，并且威斯康星大学的韦斯曼临床生物制造工厂已经生产出 cGMP HLA 纯合 iPS 细胞系。然而，这种方法的免疫学价值尚未经过临床测试。具有与人类免疫系统相似的免疫系统的动物模型。在这里，我们将使用 MHC 定义的独特食蟹猴群体来测试免疫能力对MHC纯合食蟹猴iPS细胞来源的血管细胞移植到MHC半相合的反应收件人。使用 MHC 定义的食蟹猴，我们将使用肢体缺血模型来确定 iPS 细胞来源的动脉内皮细胞移植后促进侧支循环的能力自身，与 iPS 细胞衍生的平滑肌细胞结合，或者结合成完整的组织工程动脉。该提案的一个中心前提是，正确指定的早期动脉内皮细胞将强有力地招募、扩增和成熟内源性或共移植的平滑肌细胞祖细胞增加体内动脉生成，这些动脉内皮细胞对于产生组织至关重要离体工程动脉在移植后很长时间内仍保持功能。该提案的最终目标是从 HLA 纯合人类 iPS 细胞系中生产 cGMP 血管祖细胞，用于临床前动物提交严重肢体缺血 IND 所需的研究。具有广泛的人类和灵长类动物多能干细胞专业知识、强大的生物工程部门、拥有 MHC 分型的国家灵长类动物研究中心设施和 GMP 细胞制造设施，威斯康星大学的环境非常适合以完成本提案的目标。