iPS-Glial Restricted Progenitors in White Matter Repair for Stroke

节目概要 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的死亡率正在下降。中风也因此改变 变成一种慢性残疾幸存者的疾病目前还没有促进中风康复的药物治疗。 这项提议为一种常见的中风亚型，皮质下或“白色物质”中风开发了干细胞疗法。 白色物质中风发生在大脑中进行连接的区域，是最与年龄相关的， 发病率，并且是痴呆症（称为血管性痴呆）的第二大原因。拟议的研究 表征hiPSC衍生细胞的组织整合和伤口愈合中的分子和细胞过程 在白色物质中风后的大脑修复中。该细胞由诱导的人多能细胞（hiPSC）分化而来 细胞）转化为未成熟的神经胶质细胞，并被称为hiPSC-神经胶质富集祖细胞（hiPSC-GEP）。初步 研究表明，将hiPSC-GEP移植到白色物质中风的小鼠模型中， 与其他hiPSC类型相比，这种行为恢复效果与 改善白色物质卒中的MRI表现。这项补助金中的研究将完全决定 hiPSC-GEP的表型和组织整合，hiPSC-GEP的转录谱和hiPSC-GEP的细胞， 当这两个群体在中风后随着时间的推移重新组织和相互关联时， 使用体内MRI追踪组织修复的hiPSC-GEP对中风的影响，以及hiPSC-GEP在中风中的功效 与脑卒中相关的疾病，如大脑老化。这些研究使用了一个创新的平台， 包括一种新的小鼠模型，体内MRI，Drop-seq单细胞转录谱分析和病毒报告基因， 以及功能的获得和丧失方法。拟议的研究汇集了神经科学家/神经学家， 干细胞生物学家开发一种新疗法，用于治疗一种患病率不断增加而目前没有治疗方法的疾病。

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.