Transplantation of MHC Homozygous Vascular Progenitors in Primates

灵长类 MHC 纯合血管祖细胞移植

• 批准号: 9355220
• 负责人: James Alexander Thomson
• 金额: $ 88.77万
• 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/9355220
• 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; Immunologic Tests; Immunologics; 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; animal efficacy; cGMP production; clinically relevant; combinatorial; cost; design; efficacy study; in vivo; induced pluripotent stem cell; manufacturing facility; pre-clinical; progenitor; radial artery; safety study; scaffold; tissue support frame

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，“灵长类动物中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。已经提出了从HLA等位基因纯合子的罕见个体中储存iPS细胞的方法。 作为允许规模经济的策略，同时仍然减少iPS细胞衍生的移植组织的排斥。 只有几百个这样的细胞系可以为大多数美国人提供匹配， 位于威斯康星州的魏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仍然没有得到测试， 一种免疫系统类似于人类免疫系统的动物模型。 在这里，我们将使用一个独特的群体的MHC定义的食蟹猴，以测试免疫 对MHC纯合食蟹猴iPS细胞衍生的血管细胞移植到MHC单倍体的反应 受惠人士使用MHC定义的食蟹猴，我们将使用肢体缺血模型来确定 iPS细胞衍生的动脉内皮细胞在通过血管内皮细胞移植时促进侧支循环的能力 它们本身，与iPS细胞衍生的平滑肌细胞组合，或当组合成完全组织时， 人造动脉这个建议的一个中心前提是，适当指定的早期动脉内皮细胞， 将有力地募集、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，并且这些动脉内皮细胞对于产生组织至关重要 离体工程化动脉在移植后长时间保持功能。这项提案的最终目标是 从用于临床前动物的HLA纯合人iPS细胞系产生cGMP血管祖细胞 需要提交严重肢体缺血IND的研究。具有广泛的人类和灵长类多能干细胞 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 工厂和GMP细胞制造工厂，威斯康星州大学的环境非常适合 以实现本提案的目标。