Adult neural stem cell self-regulation via soluble growth factor

成体神经干细胞通过可溶性生长因子进行自我调节

• 批准号: 1923094
• 负责人: Elizabeth Kirby
• 金额: $ 90万
• 依托单位: Ohio State University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1923094&HistoricalAwards=false
• 关键词: Adult; neural; stem; cell; self

Brain stem cells have great potential for treating neurological disorders, but this potential remains unrealized because of an incomplete understanding of how these cells maintain their immature status. In the brain of adult mammals, neural stem cells are found in a few, isolated places, including the hippocampus, where they continue to create new neurons that contribute to healthy memory function. Pilot data generated for this proposal found that adult hippocampal neural stem cells express a biochemical growth factor (vascular endothelial growth factor [VEGF]) that is essential for their long-term survival and maintenance. VEGF may act on these cells in several possible ways, and the proposed studies will determine which of these possible mechanisms VEGF uses to maintain brain stem cells. The results of this research will have a major impact on the design of stem cell-based therapies by revealing mechanisms that growth factors use to support stem cells and enhance their survival. In addition, this work will have an impact on the local community via a specialized program promoting high school stem cell education, support for a new Brain Bee outreach program, and general outreach that will educate the public about stem cell biology and its potential role in medicine. The persistence of neural stem cells (NSCs) in the adult mammalian hippocampus is highly conserved across species, yet the molecular mechanisms that regulate maintenance of these NSCs are unresolved. Numerous studies show that local signals from neighboring cells help maintain NSCs, but less attention has been given to how NSCs self-regulate. Our preliminary data show that adult hippocampal NSCs and their progenitor progeny (NSPCs) self-maintain their own stemness via expression of vascular endothelial growth factor (VEGF). While soluble proteins are classically conceptualized as signaling by binding to receptors on the cell surface, they can also act through two alternative routes that are less-frequently studied: 1) via intracrine activation of receptors in endocytic vesicles, and 2) via transmission between cells in exosomes. Pilot data show that VEGF exists in all of these cellular compartments, but which ones are essential for VEGF maintenance of stemness is unknown. The proposed experiments will use in-vitro and in-vivo murine models to determine which of these methods of VEGF transmission (paracrine extracellular, intracrine and/or paracrine exosomal) are active in NSPCs and essential for self-maintenance of stemness. The proposed work will provide a major advance in understanding for the largely uninvestigated field of non-canonical pathways for adult NSPC self-maintenance via soluble signals.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

脑干细胞具有治疗神经系统疾病的巨大潜力，但由于对这些细胞如何保持其未成熟状态的不完全理解，这种潜力仍未实现。在成年哺乳动物的大脑中，神经干细胞被发现在一些孤立的地方，包括海马体，在那里它们继续创造新的神经元，有助于健康的记忆功能。为这一提议产生的初步数据发现，成年海马神经干细胞表达一种生化生长因子（血管内皮生长因子[VEGF]），这对它们的长期存活和维持至关重要。VEGF可能以几种可能的方式作用于这些细胞，拟议的研究将确定VEGF使用这些可能的机制中的哪一种来维持脑干细胞。这项研究的结果将通过揭示生长因子用于支持干细胞并增强其存活的机制，对基于干细胞的疗法的设计产生重大影响。此外，这项工作将通过促进高中干细胞教育的专门计划，支持新的Brain Bee外展计划以及教育公众了解干细胞生物学及其在医学中的潜在作用的一般外展活动对当地社区产生影响。成年哺乳动物海马中神经干细胞（NSCs）的持续存在在物种间高度保守，但调节这些NSCs维持的分子机制尚未解决。许多研究表明，来自邻近细胞的局部信号有助于维持神经干细胞，但很少关注神经干细胞如何自我调节。我们的初步数据表明，成年海马神经干细胞和他们的祖先后代（NSPCs）通过表达血管内皮生长因子（VEGF）自我维持自己的干细胞。虽然可溶性蛋白质被经典地概念化为通过结合细胞表面上的受体进行信号传导，但它们也可以通过两种不太经常研究的替代途径起作用：1）通过内分泌激活内吞囊泡中的受体，和2）通过外泌体中的细胞之间的传递。初步数据显示，VEGF存在于所有这些细胞区室中，但哪些是VEGF维持干性所必需的尚不清楚。所提出的实验将使用体外和体内鼠模型来确定这些VEGF传递方法（旁分泌细胞外、内分泌和/或旁分泌外泌体）中的哪一种在NSPCs中是有活性的并且对于干性的自我维持是必需的。拟议的工作将提供一个重大的进步，在了解基本上未经调查的领域的非规范途径成人NSPC自我维护通过可溶性signals.This奖项反映了NSF的法定使命，并已被认为是值得通过评估使用基金会的智力价值和更广泛的影响审查标准的支持。

项目成果

Poor Concordance of Floxed Sequence Recombination in Single Neural Stem Cells: Implications for Cell Autonomous Studies

• DOI: 10.1523/eneuro.0470-19.2020
• 发表时间: 2020-03-01
• 期刊: ENEURO
• 影响因子: 3.4
• 作者: Dause, Tyler Joseph;Kirby, Elizabeth Diana
• 通讯作者: Kirby, Elizabeth Diana

Oral and injected tamoxifen alter adult hippocampal neurogenesis in female and male mice

口服和注射他莫昔芬改变雌性和雄性小鼠成年海马神经发生

• DOI: 10.1523/eneuro.0422-21.2022
• 发表时间: 2022
• 期刊: eneuro
• 影响因子: 3.4
• 作者: Smith, Bryon M.;Saulsbery, Angela I.;Sarchet, Patricia;Devasthali, Nidhi;Einstein, Dalia;Kirby, Elizabeth D.
• 通讯作者: Kirby, Elizabeth D.

The neural stem cell secretome across neurodevelopment

• DOI: 10.1016/j.expneurol.2022.114142
• 发表时间: 2022-09-01
• 期刊: EXPERIMENTAL NEUROLOGY
• 影响因子: 5.3
• 作者: Dause，Tyler J.;Denninger，Jiyeon K.;Kirby，Elizabeth D.
• 通讯作者: Kirby，Elizabeth D.