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

• 批准号: 8391654
• 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
• 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/8391654
• 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

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）： 再生医学的目的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。通常认为希望使用源自患者自身的细胞，因为这被假设为避免需要施用药物来抑制移植细胞的免疫排斥。诱导多能干细胞（iPS细胞）的发现极大地扩展了在再生医学中使用患者特异性细胞的可能性。iPS细胞可以来源于任何体细胞，但具有胚胎干细胞的特性。像胚胎细胞一样，它们可以用来产生再生医学中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得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中。在进行此类研究之前，需要进行适当的体外研究。一个主要问题是供体年龄的潜在影响。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几个优势，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。普通绒猴（Callithrix jacchus）作为一种小而易操作的NHP，已被广泛验证为生物医学模型。 在这项研究中，我们解决了几个基本的问题，必须回答细胞移植研究开始之前，在NHP。我们问：（1）供体的年龄是否会改变衍生的iPS细胞的特性，从而损害其作为多能细胞的特性？在移植到免疫缺陷小鼠体内后，分化是否正常发生，细胞是否存活并进一步分化？我们将从三个年龄组的NHP中获得iPS细胞并对其进行表征。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。为了提供一个适当分化的robut测试，我们将移植NPC到免疫缺陷小鼠的CNS中。(2)供体的年龄是否增加了存在抗分化细胞亚群的可能性，这些细胞亚群可能代表畸胎瘤发展的风险？我们将检查移植细胞在小鼠CNS中是否有长期持续的增殖。从长远来看，无论供体年龄如何，适当的分化将使增殖率降低到可以忽略的水平。(3)供体的年龄是否会影响供体的免疫细胞对iPSC衍生细胞作为自体与非自体的预期识别？预期来自一个个体供体的细胞将在体外引起与来自无关个体的免疫细胞的反应，但不引起与来自同一个体的免疫细胞的反应;无论供体年龄如何，这种正常关系在iPSC衍生的分化细胞中维持吗？ 总的来说，这些研究将使更有效的细胞疗法在未来的再生医学实施中得以提出。如果研究发现与年龄有关的缺陷，则需要采取纠正这些缺陷的策略。然而，如果从老年NHP供体产生的iPS细胞在所有方面与来自年轻供体的iPS细胞功能等同，则将在NHP模型中进行自体细胞治疗的体内测试。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，以长期测试iPSC衍生细胞的治疗潜力和安全性。