Cell-intrinsic and contextual determinants of aging by human glial progenitor cells

人类胶质祖细胞衰老的细胞内在和背景决定因素

• 批准号: 10669197
• 负责人: STEVEN Alan GOLDMAN
• 金额: $ 31.57万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669197
• 关键词: ATAC-seq; Adult; Affect; Age; Aging; Astrocytes; Back; Biology; Brain; Cell Aging; Cell Communication; Cell division; Cells; Characteristics; Chromatin; Chronic; Competence; DNA Methylation; Data; Demyelinations; Disadvantaged; Disease; Elderly; Engraftment; Environment; Epigenetic Process; Failure; Gene Expression Profile; Genes; Genetic; Genetic Suppression; Genetic Transcription; Goals; Human; In Vitro; Inflammatory; Length; Link; Longevity; Maintenance; Measures; Methylation; Mitotic; Molecular; Multiple Sclerosis; Mus; Myelin; NFIB gene; Neonatal; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Oligodendroglia; Pattern; Phenotype; Population; Process; Proliferating; RNA Sequence Analysis; RNA analysis; Recurrence; Role; Therapeutic; Time; Tissues; Transplantation; Transplantation Chimera; White Matter Disease; Work; age effect; age related; age related neurodegeneration; aged; aging brain; cell age; design; embryonic stem cell; experimental study; fetal; functional restoration; host colonization; human embryonic stem cell; in vivo; interest; knock-down; lentivirally transduced; methylation pattern; migration; myelination; neonate; neuroinflammation; overexpression; preservation; prevent; progenitor; remyelination; resilience; response; self-renewal; senescence; stem cells; transcription factor; white matter

Abstract Glial progenitor cells (GPCs) pervade the adult human brain, and can give rise to new oligodendrocytes and astrocytes in response to myelin loss; yet they may fail to do so in chronic neuroinflammatory and age- related white matter diseases. Our goal is to identify the transcriptional and epigenetic basis for age-related glial progenitor failure, with the goal of identifying the repressive transcription factors and epigenetic states that restrict progenitor cell expansion and differentiation with age. By targeting these repressive networks, we hope to restore the functional viability of human GPCs, and by so doing prevent the myelin loss that characterizes both aging and those neurodegenerative and inflammatory disorders associated with white matter disease. By so doing, we hope to preserve not only the differentiation competence of the cells, but also their self-renewal, so that myelin- ogenesis may be induced from hGPCs without the progenitor depletion to be expected of strategies designed to trigger terminal oligodendrocytic differentiation. Achieving this in human GPCs, which differ substantially in their biology from mouse, and doing so in vivo, has proven a significant challenge to the field. To this end, we will ask: 1. To what extent is the aging of human ESC-derived GPCs cell-intrinsic and linked to prior cell division, both in vitro and in vivo? What are the transcriptional and epigenetic concomitants to hGPC aging in vivo, and which of these restrict hGPC expansion and differentiation? How do hGPCs, extracted back from neonatally- transplanted human chimeric mouse brains, change in their DNA methylation patterns, their ATAC-Seq-defined patterns of chromatin accessibility, and their consequent RNA expression, over the 2-year lifespan of a mouse? 2. To what extent are the effects of aging on hGPCs a function of the aged brain environment, rather than cell autonomous? In order to define the relationship of hGPC cell age to expansion and myelination competence - and the extent to which the age of the host influences hGPC fate – these experiments will include a set of reciprocal, heterochronic transplants, grafting aged cells into neonates, and new hGPCs into aged brains. 3. In aged GPCs, can genetic knock-down of those repressors implicated in the progression to adult hGPC phenotype restore the transcriptional signature, as well as the expansion and differentiation competence in vivo, of younger hGPCs? Is suppression of MAX, potentially together with a core set of other over-expressed repressors, sufficient to restore MYC-dependent mitotic expansion and host colonization by aged hGPCs? With this work, we expect to establish a granular understanding of the relative roles of cell-intrinsic, expansion- dependent senescence and host context in regulating the proliferation and remyelination competence of human GPCs. Furthermore, if the introduction of young hGPCs into an aged environment allows the selective colonization of the host white matter by those younger hGPCs, the implications may be profound, as disorders as varied as progressive multiple sclerosis and the neurodegenerative disorders might then become potential targets of cell replacement strategies based on the competitive advantages of young over aged glial progenitors.

抽象的神经胶质祖细胞（GPC）遍布成年人的大脑，并会引起新的少突胶质细胞 和星形胶质细胞响应髓磷脂损失；然而，在慢性神经炎症和年龄 - 相关的白质疾病。我们的目标是确定与年龄相关的神经胶质的转录和表观遗传基础 祖细胞失败，目的是确定限制的反射转录因子和表观遗传状态 祖细胞的扩展和分化随着年龄的增长。通过针对这些反思性网络，我们希望恢复 人类GPC的功能可行性，通过这样做可以防止髓磷脂损失，角色都老化 以及与白质疾病相关的神经退行性和炎症性疾病。通过这样做，我们 希望不仅保留细胞的差异能力，还保留它们的自我更新，以便髓磷脂 在没有祖细胞部署的HGPC中，可能会诱导o依作用。 触发末端寡胶质细胞分化。在人类GPC中实现这一目标，在他们的GPC中有很大的不同 鼠标的生物学并在体内这样做已证明对该领域是一个重大挑战。为此，我们会问： 1。人类ESC衍生的GPC细胞内膜的衰老与先前的细胞分裂相关，在多大程度上 体外和体内都有吗？在体内HGPC衰老的转录和表观遗传伴侣是什么？ 这些限制了HGPC的扩展和分化？ HGPC如何从新生儿中提取 移植的人嵌合小鼠大脑，改变其DNA甲基化模式，其ATAC-SEQ定义 在小鼠的两年寿命中，染色质可及性及其随之而来的RNA表达的模式？ 2。衰老对HGPC的影响在多大程度上是老化的大脑环境的功能，而不是 细胞自主？为了定义HGPC细胞年龄与扩展和髓鞘能力的关系 - 宿主的年龄在多大程度上影响HGPC命运 - 这些实验将包括一组 相互，异缘移植物，将老化的细胞移植到新生儿中，并将新的HGPC分解为老化的大脑。 3。在年龄的GPC中，可以遗传敲击成人进展中的副本 HGPC表型恢复了转录签名以及扩展和分化能力 在体内，年轻的HGPC？是抑制最大的，可能与其他过表达的核心组合在一起 阻碍物，足以恢复依赖MYC的有丝分裂扩张和老年HGPC的宿主定植？ 通过这项工作，我们期望对细胞中性，扩张 - 在调节人类的增殖和延期能力时，依赖的感受和宿主环境 GPCS。此外，如果将年轻的HGPC引入年龄的环境中，则可以选择性 那些年轻的HGPC对宿主白质的殖民化，这可能是深刻的，因为疾病 随后可能会变成渐进的多发性硬化症和神经退行性疾病的变化 基于年轻的胶质神经胶质祖细胞的竞争优势，细胞替代策略的靶标。

项目成果

Lymphatic endothelial-like cells promote glioblastoma stem cell growth through cytokine-driven cholesterol metabolism.

• DOI: 10.1038/s43018-023-00658-0
• 发表时间: 2024-01
• 期刊: Nature cancer
• 影响因子: 22.7
• 作者: Linjie Zhao;Zhixin Qiu;Zhengnan Yang;Lian Xu;Thomas M Pearce;Qiulian Wu;Kailin Yang;FuLong Li;Olivier Saulnier;Fan Fei;Huaxu Yu;Ryan C. Gimple;Venkateshwari Varadharajan;Juxiu Liu;Liam D Hendrikse;Vernon Fong;Wei Wang;Jiao Zhang;Deguan Lv;Derrick Lee;Brandon M Lehrich;Chunyu Jin;Ouyang Liang;D. Dixit;Haoxing Wu;Xiang Wang;Andrew E. Sloan;Xiuxing Wang;Tao Huan;J. Mark Brown;Steven A. Goldman;Michael D Taylor;Shengtao Zhou;Jeremy N. Rich

Glial progenitor cells of the adult human white and grey matter are contextually distinct.

• DOI: 10.1002/glia.24291
• 发表时间: 2023-03
• 期刊: Glia
• 影响因子: 6.2