Neural Progenitor Grafting for Restorative Stroke Therapy

用于恢复性中风治疗的神经祖细胞移植

• 批准号: 8417716
• 负责人: Jack M Parent
• 金额: $ 31.51万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8417716
• 关键词: Acute; Address; Adult; Allografting; Antigens; Area; Attention; Autologous; Bacterial Artificial Chromosomes; Behavior; Biological Assay; Brain; Brain Diseases; Cell Line; Cell Transplants; Cells; Corpus striatum structure; Cytogenetic Analysis; Development; Environment; Fibroblasts; Gene Expression Profiling; Genes; Goals; Green Fluorescent Proteins; Growth; Hippocampus (Brain); Human; Immunosuppression; In Vitro; Infarction; Injection of therapeutic agent; Ischemia; Knowledge; Light; Methods; Modeling; Natural regeneration; Neurons; Population; Property; Rattus; Recovery; Recovery of Function; Reporter; Risk; Safety; Skin; Somatic Cell; Source; Staging; Stem cell transplant; Stroke; Surface Antigens; Techniques; Teratoma; Testing; Transcript; Transplantation; Tubulin; Xenograft procedure; base; behavior influence; cell type; functional restoration; genetic manipulation; human embryonic stem cell; human embryonic stem cell line; improved; in vivo; induced pluripotent stem cell; injured; insight; migration; nerve stem cell; nervous system disorder; neurogenesis; neuronal replacement; novel; promoter; public health relevance; regenerative therapy; repaired; restorative treatment; self-renewal; stroke therapy; subventricular zone

DESCRIPTION (provided by applicant): The overall goals of this proposal are to determine the extent to which human embryonic stem cell (hESC)- or induced pluripotent stem cell (iPSC)-derived neural progenitor cell (NPC) grafts improve recovery after experimental stroke, and to begin addressing the critical safety and efficacy questions necessary for eventual human stroke therapy. hESCs offer many advantages as a source of NPCs for regenerative therapy, such as a readily available supply, vast differentiation potential and ease of genetic manipulation. iPSCs offer the added advantage of autologous grafting that obviates the need for immunosuppression. For either source, however, the ideal donor cell types and developmental states required to achieve CNS regeneration are poorly understood. Whether NPC grafting restores function after stroke and the mechanisms by which it might do so also are unknown. We have developed methods to enrich for specific NPC populations derived from hESCs, and have generated NPCs and multiple neuronal subtypes using iPSCs derived from human fibroblasts. Using these techniques, we propose to test the following hypotheses: 1) purified populations of multipotent NPCs (mpNPCs) and neuronal restricted precursors (NRPs) can be derived from hESCs or from human somatic cells via iPSCs. These populations will differ in their migration, differentiation and integration after transplantation into the intact or injured adult rat brain; and 2) grafting of mpNPCs or NRPs after experimental stroke will enhance functional recovery directly by neuronal replacement or by stimulating repair via endogenous NPCs. Specific Aims 1 and 2 are to purify and characterize specific NPC populations using promoter-based reporter or cell surface antigen-based selection. Aim 3 is to examine the behavior of these NPC populations after grafting into neurogenic and non-neurogenic regions of the adult rat brain, and Aim 4 is to examine the influence of hESC- and iPSC (human and rat)-derived NPC grafts on recovery after experimental stroke. Progress in these aims will advance our knowledge of how graft factors influence the capacity of hESC- or iPSC-derived NPCs to repair the injured brain and promote recovery after experimental stroke, and will provide insight into the untapped reparative potential and possible risks of these therapies.

描述(申请人提供)：这项提案的总体目标是确定人类胚胎干细胞(HESC)或诱导多能干细胞(IPSC)来源的神经前体细胞(NPC)移植在多大程度上改善实验性中风后的康复，并开始解决最终人类中风治疗所必需的关键安全性和有效性问题。人类胚胎干细胞作为再生治疗的神经前体细胞来源具有许多优点，例如容易获得的来源、巨大的分化潜力和易于基因操作。IPSCs提供了自体移植的额外优势，不需要免疫抑制。然而，对于任何一种来源，实现中枢神经系统再生所需的理想供体细胞类型和发育状态都知之甚少。鼻咽癌移植是否能恢复中风后的功能，以及可能的机制也是未知的。我们已经开发了丰富hESCs来源的特定NPC群体的方法，并使用来自人成纤维细胞的IPSCs产生了NPC和多种神经元亚型。利用这些技术，我们提出了以下假设：1)多能神经前体细胞(MpNPC)和神经元限制性前体细胞(NRPs)的纯化群体可以从hESCs或通过IPSCs从人体细胞获得。这些群体在移植到完整或损伤的成年大鼠脑内后，在迁移、分化和整合方面将有所不同；2)实验性卒中后移植mpNPC或NRPs将直接通过神经元替代或通过内源性NPC刺激修复来促进功能恢复。具体目标1和2是利用基于启动子的报告基因或基于细胞表面抗原的选择来纯化和鉴定特定的鼻咽癌群体。目的3是研究这些鼻咽癌群体移植到成年大鼠脑内神经源性和非神经源性区域后的行为，目的4是研究hESC和IPSC来源的鼻咽癌移植对实验性卒中后康复的影响。在这些目标方面的进展将促进我们对移植因素如何影响hESC或IPSC来源的神经干细胞修复受损大脑和促进实验性中风后康复的能力的了解，并将提供对这些疗法尚未开发的修复潜力和可能的风险的洞察。