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.

摘要胶质祖细胞广泛存在于成年人大脑中，可分化为新的少突胶质细胞 和星形胶质细胞对髓鞘丢失的反应;然而，在慢性神经炎和年龄- 相关的白色物质疾病。我们的目标是确定与年龄相关的神经胶质细胞的转录和表观遗传基础， 祖细胞失败，目的是确定抑制转录因子和表观遗传状态， 祖细胞扩增和随年龄的分化。通过打击这些压制性网络，我们希望恢复 人类GPCs的功能活力，并通过这样做来防止髓鞘丢失， 以及那些与白色物质疾病相关的神经变性和炎性疾病。通过这样做，我们 希望不仅能保持细胞的分化能力，还能保持它们的自我更新，这样髓鞘- 可以从hGPCs诱导发生，而不需要预期的设计策略的祖细胞消耗， 触发末端少突胶质细胞分化。在人类GPCs中实现这一点，这些GPCs在其功能上有很大不同。 来自小鼠的生物学以及在体内这样做已被证明是对该领域的重大挑战。为此，我们将问： 1.人ESC衍生的GPCs的衰老在多大程度上是细胞内在的，并与先前的细胞分裂有关， 在体外和体内都是如此吗什么是转录和表观遗传伴随hGPC在体内老化， 这些限制hGPC的扩展和分化？如何做hGPCs，提取回从子宫- 移植的人类嵌合小鼠大脑，其DNA甲基化模式的变化，其ATAC-Seq定义的 在小鼠2年的寿命中，染色质可及性的模式及其随之而来的RNA表达？ 2.衰老对hGPCs的影响在多大程度上是衰老大脑环境的功能，而不是 细胞自主？为了确定hGPC细胞年龄与扩增和髓鞘形成能力的关系， - 以及宿主年龄影响hGPC命运的程度-这些实验将包括一组 相互异时移植，将老化细胞移植到新生儿中，以及将新的hGPCs移植到老化的大脑中。 3.在老年GPCs中，基因敲低那些与向成年GPCs进展有关的阻遏物， hGPC表型恢复转录特征，以及扩增和分化能力 在体内，年轻的hGPCs？是MAX的抑制，可能与其他过度表达的核心集一起 阻遏物，足以恢复MYC依赖的有丝分裂扩增和宿主定植的老年hGPCs？ 通过这项工作，我们希望建立一个颗粒的理解细胞的相对作用，内在的，扩展， 依赖性衰老和宿主环境在调节人神经细胞增殖和髓鞘再生能力中的作用 GPC。此外，如果将年轻的hGPCs引入到老化的环境中允许选择性的生长， 这些年轻的hGPCs在宿主白色物质中的定植，其影响可能是深远的， 进行性多发性硬化症和神经退行性疾病可能成为潜在的 基于年轻的胶质祖细胞相对于老年胶质祖细胞的竞争优势的细胞替代策略的靶点。

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