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.

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 已提出从 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，而且 威斯康星大学的韦斯曼临床生物制造工厂已经生产出 cGMP 然而，这种方法的免疫学价值尚未在 HLA 纯合 iPS 细胞系中进行测试。 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 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 本身，与 iPS 细胞衍生的平滑肌细胞结合，或结合成完整的组织 该提议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 该提案的最终目标是离体工程动脉在移植后长期保持功能。 从 HLA 纯合人 iPS 细胞系生产 cGMP 血管祖细胞，用于临床前动物 需要针对严重肢体缺血提交 IND 的研究，涉及广泛的人类和灵长类多能干。 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。