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: 8241495
• 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/8241495
• 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. PUBLIC HEALTH RELEVANCE: Veterans are among the many US Citizens who may benefit from the application of regenerative medicine to the therapy of human disease. In the future, regenerative medicine may offer better regeneration of organs that have suffered damage from trauma in combat or other events, and better approaches to the therapy of degenerative diseases that impair function and shorten life in older Veterans. An important discovery for regenerative medicine is induced pluripotent stem (iPS) cells. iPS cells are like embryonic stem cells, yet can be derived from any adult cell, such as a skin cell. When iPS cells are derived from the skin cells of an individual patient, they should be able to be transplanted back to the same patient without rejection. Before this is applied to human patients, the properties of iPS cells must be thoroughly explored in suitable animal models, to make sure that autologous cell therapy is both safe and effective. For this purpose nonhuman primates are ideal, because of their relatedness to humans and their similar central nervous systems.

描述（由申请人提供）： 再生医学的目的是恢复受疾病或衰老受损的器官的健康功能。一个主要问题是用于再生医学中的细胞来源。人们通常认为使用从患者本人中获得的细胞是可取的，因为假设这是为了避免使用药物以抑制移植细胞的免疫排斥的需要。通过发现诱导的多能干细胞（IPS细胞），在再生医学中使用患者特异性细胞的可能性大大扩展了。 IPS细胞可以源自任何体细胞，但具有胚胎干细胞的特性。像胚胎细胞一样，它们可用于生成在再生医学中可能需要的任何细胞。 这些研究的最终目的是在IPS细胞向特定细胞谱系的指示分化后，从单个动物中得出IPS细胞，并将细胞植入供体动物。在进行此类研究之前，需要进行适当的体外研究。一个主要的问题涉及捐助者年龄的潜在影响。大多数将成为这种治疗形式的候选者的患者会年龄较大，或者至少是成年人。非人类灵长类动物（NHP）为IPS细胞及其分化后代（包括供体年龄的作用）提供了几个优势。这些优势包括与人类的遗传相关性，并类似地发展了中枢神经系统。作为一个易于处理的小型NHP，普通的marmoset（Callithrix jacchus）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问​​题，这些问题必须在NHP中开始细胞移植研究开始之前必须回答。我们问：（1）供体的年龄是否会改变衍生的IPS细胞的性质，从而损害其特性作为多能细胞？分化是否正常发生，在免疫缺陷小鼠中植入后，细胞是否可以生存并经历进一步的分化？我们将从三个年龄组的NHP中得出并表征IPS细胞。经过多能性测试，我们将评估每个IPS细胞系与神经祖细胞（NPC）区分开的能力。为了提供适当的分化的体测试，我们将将NPC移植到免疫缺陷小鼠的中枢神经中心。 （2）捐助者的年龄是否增加了可能代表畸胎瘤发育风险的细胞抗性亚群的可能性？我们将检查小鼠中枢神经系统中移植细胞的长期持续增殖。可以预期，无论供体年龄如何，长期的适当分化将使增殖率降低到可忽略不计的水平。 （3）捐赠者的年龄是否会影响IPSC衍生细胞的预期识别为自我与供体免疫细胞的非自然识别？预计来自一个供体的细胞将在不相关个体的免疫细胞中引起反应，而不会与来自同一个体的免疫细胞产生反应。在IPSC衍生的分化细胞中是否保持这种正常关系，无论供体年龄如何？ 总的来说，这些研究将使未来再生医学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，则需要采取纠正此类缺陷的策略。但是，如果从老年NHP供体产生的IPS细胞在各个方面都与年轻捐赠者的功能等效，则自体细胞疗法的体内测试将在NHP模型中进行。未来的研究将涉及在长期测试IPSC衍生细胞的治疗潜力和安全性的长期测试中，将源自IPS细胞的分化细胞移植到供体动物中。 公共卫生相关性： 退伍军人是许多美国公民之一，他们可能从将再生医学应用于人类疾病治疗中受益。将来，再生医学可能会更好地再生，这些器官在战斗或其他事件中遭受创伤损害的器官，以及更好地治疗退化性疾病的治疗方法，这些疾病会损害老年退伍军人的寿命和缩短寿命。再生医学的重要发现是诱导多能干（IPS）细胞。 IPS细胞就像胚胎干细胞一样，但可以源自任何成年细胞，例如皮肤细胞。当IPS细胞源自单个患者的皮肤细胞时，应能够将它们移植回同一患者而不会排斥。在将其应用于人类患者之前，必须在合适的动物模型中彻底探索IPS细胞的特性，以确保自体细胞疗法既安全有效又有效。为此，非人类灵长类动物是理想的，因为它们与人类及其类似的中枢神经系统的关系。