iPS-Glial Restricted Progenitors in White Matter Repair for Stroke

计划摘要 中风是成人残疾的主要原因。随着人口老龄化，中风的发病率也在增加。 急性中风护理的改善意味着中风死亡率正在下降。因此，中风已经改变了 变成了一种长期残疾幸存者的疾病。目前还没有促进中风患者康复的药物疗法。 这项提议为中风、皮质下或“白质”中风的一种常见亚型开发了一种干细胞疗法。 白质卒中发生在大脑中承载连接的区域，是其年龄相关性最大的 它是导致痴呆症(称为血管性痴呆)的第二大原因。建议进行的研究 表征hPSC来源细胞在组织整合和伤口愈合中的分子和细胞过程 在脑白质中风后的大脑修复中。这种细胞是从诱导的人类多能细胞(HiPSC)分化而来的 细胞)分化为未成熟的神经胶质细胞，称为神经胶质细胞富集祖细胞(hiPSC-GEP)。初步 研究表明，将HiPSC-GEP移植到白质卒中小鼠模型中可增强 与其他类型的HiPSC相比，这种行为恢复效果与 脑白质卒中MRI表现的改善。这笔赠款中的研究将完全决定 HIPS-GEPs的表型和组织整合、HIPSC-GEPs的转录图谱和HIPS-GEPs的细胞 随着中风后这两个群体随着时间的推移重新组织和相互联系，周围的中风环境 体内MRI示踪组织修复的HiPSC-GEPs对卒中的影响及在卒中的疗效 翻译相关的中风情况，例如在老化的大脑中。这些研究使用了一个创新的平台 这包括一种新的小鼠模型、活体核磁共振、Drop-Seq单细胞转录图谱和病毒报告 以及函数的得失方法。拟议的研究汇集了一位神经学家/神经学家和 干细胞生物学家开发一种新的治疗这种疾病的方法，这种疾病的流行率越来越高，目前还没有治疗方法。

Program Summary Stroke is the leading cause of adult disability. As the population ages, the incidence of stroke is increasing. Improvements in acute stroke care mean that the death rate from stroke is declining. Stroke has thus changed into a disease of chronically disabled survivors. There is no medical therapy that promotes recovery in stroke. This proposal develops a stem cell therapy for a common subtype of stroke, subcortical or “white matter” stroke. White matter stroke occurs in the regions of the brain that carry connections, is the most age-associated in its incidence, and is the second leading cause of dementia (termed vascular dementia). The proposed studies characterize the molecular and cellular process in tissue integration and wound healing of an hiPSC-derived cell in brain repair after white matter stroke. This cell is differentiated from an induced human pluripotent cell (hiPSC cell) into an immature glial cell, and is termed an hiPSC-glia enriched progenitor (hiPSC-GEP). Preliminary studies indicate that transplantation of hiPSC-GEPs into a mouse model of white matter stroke enhances behavioral recovery compared to other hiPSC types, and that this behavioral recovery effect is associated with improvement in the MRI appearance of white matter stroke. The studies in this grant will fully determine the phenotype and tissue integration of hiPS-GEPs, the transcriptional profile of hiPSC-GEPs and the cells of the surrounding stroke environment as these two populations re-organize and inter-relate over time after stroke, the effect of hiPSC-GEPs on stroke using in vivo MRI to track tissue repair, and the efficacy of hiPSC-GEPs in translationally relevant stroke conditions, such as in the aging brain. These studies use an innovative platform that includes a new mouse model, in vivo MRI, Drop-seq single cell transcriptional profiling, and viral reporter and gain and loss of function approaches. The proposed studies bring together a neuroscientist/neurologist and stem cell biologist to develop a novel therapy in a disease with increasing prevalence and no current therapy.