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：
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
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/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

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，“私人中MHC纯合血管祖细胞的移植。” 对于组织工程动脉，随着时间的推移，使用特定患者IPS细胞的使用将受到严重限制约束和成本。已经提出了来自HLA等位基因纯合子的稀有个体的银行IPS细胞作为允许规模经济的策略，同时仍减少对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口提供匹配，以及威斯康星大学的Waisman临床生物制造设施已经产生了CGMP HLA纯合IPS细胞系。但是，这种方法的免疫学价值仍未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，我们将使用独特的MHC定义的Cynomolgus猴子来测试免疫对MHC纯合cynomolgus IPS细胞衍生的血管细胞的反应收件人。使用MHC定义的Cynomolgus猴子，我们将使用肢体缺血模型来确定 IPS细胞衍生的手工质的内皮细胞的能力在移植时有助于附带循环本身，与IPS细胞衍生的平滑肌细胞结合使用，或组合成完全组织工程动脉。该提议的一个主要前提是正确指定的早期人工伪像内皮细胞将坚强地招募，扩展和成熟的内源性或共同移植的平滑肌细胞祖细胞到增加体内动脉生成，这些动脉内皮细胞对于产生组织至关重要移植后很长时间保持功能性的工程动脉。该提议的最终目标是从HLA纯合的人IPS细胞系中产生CGMP血管祖细胞，用于临床前动物为关键的肢体缺血提交IND所需的研究。具有广泛的人类和灵长类动物的茎 Cell专业知识，强大的生物工程系，国家灵长类动物研究中心，MHC打字威斯康星大学的环境非常适合，设施和GMP细胞制造设施非常适合完成该提案的目标。