3274 – DEVELOPMENTAL PROGRAMMING OF HEMATOPOIETIC STEM CELL DORMANCY THROUGH EVASION OF NOTCH SIGNALING

IF 2.7 4区医学 Q2 HEMATOLOGY

Experimental hematology Pub Date : 2026-10-01 Epub Date: 2026-10-23 DOI:10.1016/j.exphem.2026.105878

Patricia Herrero Molinero, Eric Cantón, María Maqueda, Cristina Ruiz-Herguido, Arnau Iglesias, Jessica González, Brandon Hadland, Lluís Espinosa, Anna Bigas

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引用次数: 0

Abstract

Dormant hematopoietic stem cells (HSCs) are deeply quiescent, metabolically restrained cells that sustain lifelong hematopoiesis, yet when and how this state is established remains unclear. In mice, dormancy has been proposed to arise postnatally in the bone marrow, whereas fetal liver HSCs are generally considered uniformly proliferative. Here, we investigated whether HSC dormancy is instead established during embryogenesis. Using inducible histone H2B fused with green fluorescent protein (H2B-GFP) for long-term label retention, transcriptomics, and competitive transplantation assays, we identified a rare low-dividing HSC population specified during embryonic development that persists into adulthood. Analysis of single-cell data from human fetal liver reveals a transcriptionally analogous HSC population expressing a dormant signature. Mechanistically, we find that Notch signaling drives HSC activation in the fetal liver, whereas cells that evade Notch input adopt a dormant state. Genetic and pharmacological perturbations reveal a defined developmental window in which transient reduction of Notch exposure promotes quiescence and enhances long-term repopulating capacity, whereas sustained Notch inhibition impairs HSC function. Equivalent Notch modulation in adult HSCs fails to induce dormancy. These findings demonstrated that HSC dormancy is established during embryonic development and uncover a temporally restricted role for Notch signaling in programming lifelong stem cell behavior.

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3274 -通过逃避notch信号的造血干细胞休眠的发育编程

休眠造血干细胞（hsc）是一种深度静止、代谢受限的细胞，可维持终身造血功能，但这种状态何时以及如何建立尚不清楚。在小鼠中，骨髓休眠被认为是在出生后出现的，而胎儿肝造血干细胞通常被认为是均匀增殖的。在这里，我们研究了HSC休眠是否在胚胎发生期间建立。利用诱导组蛋白H2B与绿色荧光蛋白（H2B- gfp）融合进行长期标记保留、转录组学和竞争性移植分析，我们发现了一种罕见的低分裂HSC群体，这种群体在胚胎发育期间被指定，并持续到成年。对人类胎儿肝脏单细胞数据的分析揭示了一个转录类似的表达休眠特征的HSC群体。在机制上，我们发现Notch信号驱动胎儿肝脏中的HSC激活，而逃避Notch输入的细胞则处于休眠状态。遗传和药理学扰动揭示了一个确定的发育窗口，其中Notch暴露的短暂减少促进了静止并增强了长期的再繁殖能力，而持续的Notch抑制损害了HSC的功能。成人造血干细胞的等效Notch调节不能诱导休眠。这些发现表明，HSC休眠是在胚胎发育过程中建立的，并揭示了Notch信号在编程终身干细胞行为中的暂时限制作用。休眠造血干细胞（hsc）是一种深度静止、代谢受限的细胞，可维持终身造血功能，但这种状态何时以及如何建立尚不清楚。在小鼠中，骨髓休眠被认为是在出生后出现的，而胎儿肝造血干细胞通常被认为是均匀增殖的。在这里，我们研究了HSC休眠是否在胚胎发生期间建立。利用诱导组蛋白H2B与绿色荧光蛋白（H2B- gfp）融合进行长期标记保留、转录组学和竞争性移植分析，我们发现了一种罕见的低分裂HSC群体，这种群体在胚胎发育期间被指定，并持续到成年。对人类胎儿肝脏单细胞数据的分析揭示了一个转录类似的表达休眠特征的HSC群体。在机制上，我们发现Notch信号驱动胎儿肝脏中的HSC激活，而逃避Notch输入的细胞则处于休眠状态。遗传和药理学扰动揭示了一个确定的发育窗口，其中Notch暴露的短暂减少促进了静止并增强了长期的再繁殖能力，而持续的Notch抑制损害了HSC的功能。成人造血干细胞的等效Notch调节不能诱导休眠。这些发现表明，HSC休眠是在胚胎发育过程中建立的，并揭示了Notch信号在编程终身干细胞行为中的暂时限制作用。

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来源期刊

Experimental hematology 医学-血液学

CiteScore

5.30

自引率

0.00%

发文量

审稿时长

58 days

期刊介绍： Experimental Hematology publishes new findings, methodologies, reviews and perspectives in all areas of hematology and immune cell formation on a monthly basis that may include Special Issues on particular topics of current interest. The overall goal is to report new insights into how normal blood cells are produced, how their production is normally regulated, mechanisms that contribute to hematological diseases and new approaches to their treatment. Specific topics may include relevant developmental and aging processes, stem cell biology, analyses of intrinsic and extrinsic regulatory mechanisms, in vitro behavior of primary cells, clonal tracking, molecular and omics analyses, metabolism, epigenetics, bioengineering approaches, studies in model organisms, novel clinical observations, transplantation biology and new therapeutic avenues.