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（由申请人提供）：该提案的总体目标是确定人胚胎干细胞（hESC）或诱导多能干细胞（iPSC）衍生的神经祖细胞（NPC）移植物在多大程度上改善实验性中风后的恢复，并开始解决最终人类中风治疗所需的关键安全性和有效性问题。 hESC 作为用于再生治疗的 NPC 来源具有许多优势，例如易于获得的供应、巨大的分化潜力和易于基因操作。 iPSC 具有自体移植的额外优势，无需免疫抑制。然而，对于这两种来源，人们对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知之甚少。 NPC 移植是否能在中风后恢复功能及其机制尚不清楚。我们开发了方法来富集源自 hESC 的特定 NPC 群体，并使用源自人成纤维细胞的 iPSC 生成了 NPC 和多种神经元亚型。使用这些技术，我们建议测试以下假设：1）纯化的多能NPC（mpNPC）和神经元限制性前体（NRP）群体可以源自hESC或通过iPSC源自人类体细胞。这些群体在移植到完整或受伤的成年大鼠大脑后，其迁移、分化和整合方面会有所不同； 2) 实验性中风后移植 mpNPC 或 NRP 将通过神经元替代或通过内源性 NPC 刺激修复直接增强功能恢复。具体目标 1 和 2 是使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表征特定的 NPC 群体。目标 3 是检查这些 NPC 群体在移植到成年大鼠大脑的神经源性和非神经源性区域后的行为，目标 4 是检查 hESC 和 iPSC（人类和大鼠）来源的 NPC 移植物对恢复的影响实验性中风后。这些目标的进展将加深我们对移植因子如何影响 hESC 或 iPSC 衍生的 NPC 修复受损大脑和促进实验性中风后恢复的能力的了解，并将深入了解这些疗法尚未开发的修复潜力和可能的风险。