Transplantation of MHC Homozygous Vascular Progenitors in Primates

灵长类 MHC 纯合血管祖细胞移植

• 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
• 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

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，“在灵长类动物中移植MHC纯合子血管前体细胞”。 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格限制。 约束和成本。已提出将罕见的人类白细胞抗原纯合子个体的iPS细胞存入银行 作为一种战略，允许规模经济，同时仍然减少iPS细胞来源的移植组织的排斥反应。 只有几百个这样的细胞系可以为大多数美国人提供匹配，而 威斯康星大学的韦斯曼临床生物制造设施已经生产出cGMP HL A纯合子iPS细胞株。然而，这种方法的免疫学价值仍未在 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MHC定义的独特种群的食蟹猴来测试免疫力 MHC纯合型食蟹猴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 与iPS细胞衍生的平滑肌细胞结合，或结合成完整的组织 人造动脉。这一提议的一个中心前提是适当指定早期动脉内皮细胞 将大力招募、扩增和成熟内源性或联合移植的平滑肌细胞前体细胞以 增加体内动脉的生成，这些动脉内皮细胞将是产生组织的关键 在移植后很长一段时间内仍保持功能的体外工程动脉。这项提议的最终目标是 从人类白细胞抗原纯合子人iPS细胞系中扩增cGMP血管祖细胞用于临床前动物 为严重肢体缺血提交IND所需的研究。具有广泛的人类和灵长类多能性干细胞 细胞专业知识，强大的生物工程系，拥有MHC分型的国家灵长类研究中心 设施和GMP细胞制造设施，威斯康星大学的环境非常适合 完成这项提案的目标。