Nonhuman primate induced pluripotent stem cells in regenerative medicine

非人灵长类动物诱导多能干细胞在再生医学中的应用

基本信息

批准号：
8760300
负责人：
PETER J HORNSBY
金额：
--
依托单位：
SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-10-01 至 2015-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8760300
关键词：
Address Adult Affect Age Aging Animal Model Animals Autologous Back Biopsy Callithrix Callithrix jacchus jacchus Cell Line Cell Lineage Cell Therapy Cell Transplantation Cell Transplants Cell division Cells Characteristics Defect Degenerative Disorder Development Disease Event Exhibits Fibroblasts Future Generations Genetic Germ Layers Goals Graft Rejection Human Immune Immune system Immunodeficient Mouse Implant In Vitro Individual Investigation Life Lymphocyte MHC Class I Genes Modeling Mus Natural Killer Cells Neuraxis Neurons Oligodendroglia Organ Patients Pharmaceutical Preparations Phase Population Probability Production Property Proteins Protocols documentation Reaction Regenerative Medicine Research Research Personnel Resistance Risk Rodent Model Role Safety Skin Somatic Cell Source Teratoma Testing Therapeutic Therapeutic Effect Tissues Transplantation Trauma Up-Regulation Veterans age group age related antigen processing base blastomere structure combat cytokine embryonic stem cell human disease immunogenicity implantation improved in vivo induced pluripotent stem cell middle age nerve stem cell neuronal cell body nonhuman primate organ regeneration pluripotency preclinical study relating to nervous system research study response translational study

项目摘要

DESCRIPTION (provided by applicant): The aims of regenerative medicine are to restore healthy function to organs damaged by disease or aging. A major issue is the source of cells to be used in regenerative medicine. It is often thought to be desirable to use cells derived from the patient himself/herself, because this is hypothesized to avoid the need to administer drugs to suppress immune rejection of the transplanted cells. The possibility of using patient- specific cells in regenerative medicine was greatly expanded by the discovery of induced pluripotent stem cells (iPS cells). iPS cells can be derived from any somatic cell, but have the properties of embryonic stem cells. Like embryonic cells, they can be used to generate any cell of the body that may be needed in regenerative medicine. The eventual goal of these studies is to derive iPS cells from individual animals and implant the cells into the donor animal following the directed differentiation of the iPS cells to specific cell lineages. Before such studies are possible, appropriate in vitro investigations are needed. A major question concerns the potential impact of donor age. Most patients who would be candidates for this form of therapy would be older, or, at least, mature adults. Nonhuman primates (NHPs) offer several advantages for basic and preclinical studies of iPS cells and their differentiated progeny, including the role of donor age. These advantages include genetic relatedness to humans, and similarly developed central nervous systems. The common marmoset (Callithrix jacchus), as a small, easily handled NHP, has been extensively validated as a biomedical model. In this research, we address several basic questions that must be answered before cell transplantation studies commence in NHPs. We ask: (1) Does the age of the donor change the properties of the derived iPS cells, impairing their properties as pluripotent cells? Does differentiation occur normally, and do the cells survive and undergo further differentiation following implantation in immunodeficient mice? We will derive and characterize iPS cells from NHPs of three age groups. Following tests of pluripotency, we will assess the ability of each iPS cell line to differentiate to neural progenitor cells (NPCs). To provide a robut test of proper differentiation, we will transplant NPCs into the CNS of immunodeficient mice. (2) Does the age of the donor increase the probability of the existence of a differentiation-resistant subpopulation of cells that could represent a risk for teratoma development? We will examine if there is long-term continued proliferation of transplanted cells in the mouse CNS. It is expected that appropriate differentiation will have reduced the rate of proliferation to negligible levels oer the long term, irrespective of donor age. (3) Does the age of the donor affect the expected recognition of the iPSC-derived cells as self versus nonself by immune cells of the donor? It is expected that the cells from one individual donor will elicit a reaction in vitro with immune cells from unrelated individuals, but not with immune cells from the same individual; is this normal relationship maintained in iPSC-derived differentiated cells, irrespective of donor age? Collectively, these studies will enable more effective cell therapy to be proposed in future implementations of regenerative medicine. If the studies reveal age-related defects, strategies to correct such defects will be required. However, if iPS cells generated from older NHP donors function equivalently to those from younger donors in all respects, in vivo tests of autologous cell therapy will proceed in the NHP model. Future studies would involve the transplantation of differentiated cells derived from iPS cells back into the donor animal, in long-term tests of the therapeutic potential and safety of iPSC-derived cells.

描述（由申请人提供）：再生医学的目标是恢复因疾病或衰老而受损的器官的健康功能。一个主要问题是用于再生医学的细胞来源。通常认为使用源自患者自身的细胞是可取的，因为假设这可以避免需要施用药物来抑制移植细胞的免疫排斥。诱导性多能干细胞（iPS 细胞）的发现大大扩展了在再生医学中使用患者特异性细胞的可能性。 iPS 细胞可以源自任何体细胞，但具有胚胎干细胞的特性。与胚胎细胞一样，它们可用于生成再生医学可能需要的任何身体细胞。这些研究的最终目标是从个体动物中获取 iPS 细胞，并在 iPS 细胞定向分化为特定细胞谱系后将细胞植入供体动物体内。在进行此类研究之前，需要进行适当的体外研究。一个主要问题涉及捐赠者年龄的潜在影响。大多数适合这种疗法的患者都是老年人，或者至少是成熟的成年人。非人灵长类动物 (NHP) 为 iPS 细胞及其分化后代的基础和临床前研究提供了多种优势，包括供体年龄的作用。这些优势包括与人类的遗传相关性以及类似发达的中枢神经系统。普通狨猴 (Callithrix jacchus) 作为一种小型、易于处理的 NHP，作为生物医学模型已得到广泛验证。在这项研究中，我们解决了在 NHP 中开始细胞移植研究之前必须回答的几个基本问题。我们问：(1) 供体的年龄是否会改变衍生 iPS 细胞的特性，从而损害其作为多能细胞的特性？分化是否正常发生，细胞在植入免疫缺陷小鼠体内后是否能存活并进一步分化？我们将从三个年龄组的 NHP 中衍生并表征 iPS 细胞。在多能性测试之后，我们将评估每个 iPS 细胞系分化为神经祖细胞 (NPC) 的能力。为了提供正确分化的稳健测试，我们将 NPC 移植到免疫缺陷小鼠的 CNS 中。 (2) 捐献者的年龄是否会增加存在抗分化细胞亚群的可能性，而这种细胞亚群可能代表畸胎瘤形成的风险？我们将检查小鼠中枢神经系统中移植细胞是否长期持续增殖。预计从长远来看，适当的分化将把增殖率降低到可忽略的水平，而与供体年龄无关。 (3) 供体的年龄是否会影响供体免疫细胞对 iPSC 衍生细胞作为自身细胞和非自身细胞的预期识别？预计来自一个个体供体的细胞将在体外与来自无关个体的免疫细胞引起反应，但不会与来自同一个体的免疫细胞发生反应；无论供体年龄如何，这种正常关系在 iPSC 衍生的分化细胞中是否保持？总的来说，这些研究将使在未来再生医学的实施中提出更有效的细胞疗法。如果研究揭示了与年龄相关的缺陷，则需要采取策略来纠正这些缺陷。然而，如果老年 NHP 捐赠者产生的 iPS 细胞在各方面与年轻捐赠者产生的 iPS 细胞功能相同，那么自体细胞疗法的体内测试将在 NHP 模型中进行。未来的研究将涉及将 iPS 细胞衍生的分化细胞移植回供体动物体内，以长期测试 iPSC 衍生细胞的治疗潜力和安全性。