1004 – ESTABLISHING AND MAINTAINING THE HUMAN HEMATOPOIETIC STEM CELL PROGRAM

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.2026.105500

Vincenzo Calvanese

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引用次数: 0

Abstract

Hematopoietic stem cells (HSCs) sustain lifelong blood production through self-renewal and multilineage differentiation. Despite their central role in health and disease, the molecular mechanisms that establish and preserve the human HSC program remain poorly understood, limiting our ability to generate or expand HSCs for clinical use.

Our work has approached this challenge from complementary angles. Previous single-cell mapping of human HSCs from the first trimester to birth had revealed a conserved HSC signature (including myeloid/lymphoid or mixed-lineage leukemia; translocated to, 3/AF9 [MLLT3] and hepatic leukemia factor [HLF]) that tracks their emergence and maturation across developmental niches. Building on this framework, we now addressed two fundamental questions: how the mature HSC program is established during development and how it is maintained.

Longitudinal single-nucleus multiomic profiling of human fetal HSCs revealed transcriptional and chromatin-level modifications accompanying maturation across developmental stages. Complementary spatial analysis allowed definition of the microenvironmental cues that support this process. Paired analysis of fetal liver and fetal bone marrow HSCs uncovered remodeling of HSC metabolism and lineage priming, together with dynamic niche changes associated with HSC relocation.

To understand how HSC identity is maintained, we further investigated key regulators within the HSC transcriptional network. Mechanistic studies of MLLT3 established transcriptional pausing and elongation as central to HSC function; tuning these processes through cyclin-dependent kinase 9 (CDK9) inhibition preserves HSC identity in ex vivo expansion and improves long-term engraftment. In addition, isoform-specific dissection of HLF revealed precise chromatin regulation sustaining HSC self-renewal.

Together, we described a model in which HSC function emerges through the coordinated action of developmental programs, specialized microenvironments, and transcriptional regulatory mechanisms. Defining the molecular grammar of human stemness may ultimately enable the rational generation, expansion, and therapeutic manipulation of HSCs in regenerative medicine and leukemia.

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1004 -建立和维持人类造血干细胞计划

造血干细胞（hsc）通过自我更新和多谱系分化维持终身血液生产。尽管它们在健康和疾病中发挥着核心作用，但建立和保存人类HSC程序的分子机制仍然知之甚少，这限制了我们产生或扩展临床使用HSC的能力。我们的工作从互补的角度来应对这一挑战。先前从妊娠早期到出生的人类HSC单细胞图谱揭示了保守的HSC特征（包括髓系/淋巴系或混合谱系白血病；易位为，3/AF9 [MLLT3]和肝性白血病因子[HLF]），可以追踪它们在发育小生境中的出现和成熟。在这个框架的基础上，我们现在解决了两个基本问题：在开发过程中如何建立成熟的HSC计划以及如何维护它。人类胎儿造血干细胞的纵向单核多组学分析显示，随着发育阶段的成熟，转录和染色质水平发生了变化。互补空间分析允许定义支持这一过程的微环境线索。对胎儿肝脏和胎儿骨髓造血干细胞的配对分析揭示了造血干细胞代谢和谱系启动的重塑，以及与造血干细胞重新定位相关的动态生态位变化。为了了解HSC身份是如何维持的，我们进一步研究了HSC转录网络中的关键调控因子。MLLT3的机制研究表明，转录暂停和延长是HSC功能的核心；通过抑制细胞周期蛋白依赖性激酶9 （CDK9）调节这些过程，在体外扩增中保持HSC的身份，并改善长期植入。此外，对HLF的异构体特异性解剖揭示了维持HSC自我更新的精确染色质调控。总之，我们描述了一个模型，在这个模型中，HSC功能通过发育程序、专门的微环境和转录调节机制的协调作用而出现。定义人类干细胞的分子语法可能最终使造血干细胞在再生医学和白血病中的合理产生、扩展和治疗操作成为可能。造血干细胞（hsc）通过自我更新和多谱系分化维持终身血液生产。尽管它们在健康和疾病中发挥着核心作用，但建立和保存人类HSC程序的分子机制仍然知之甚少，这限制了我们产生或扩展临床使用HSC的能力。我们的工作从互补的角度来应对这一挑战。先前从妊娠早期到出生的人类HSC单细胞图谱揭示了保守的HSC特征（包括髓系/淋巴系或混合谱系白血病；易位为，3/AF9 [MLLT3]和肝性白血病因子[HLF]），可以追踪它们在发育小生境中的出现和成熟。在这个框架的基础上，我们现在解决了两个基本问题：在开发过程中如何建立成熟的HSC计划以及如何维护它。人类胎儿造血干细胞的纵向单核多组学分析显示，随着发育阶段的成熟，转录和染色质水平发生了变化。互补空间分析允许定义支持这一过程的微环境线索。对胎儿肝脏和胎儿骨髓造血干细胞的配对分析揭示了造血干细胞代谢和谱系启动的重塑，以及与造血干细胞重新定位相关的动态生态位变化。为了了解HSC身份是如何维持的，我们进一步研究了HSC转录网络中的关键调控因子。MLLT3的机制研究表明，转录暂停和延长是HSC功能的核心；通过抑制细胞周期蛋白依赖性激酶9 （CDK9）调节这些过程，在体外扩增中保持HSC的身份，并改善长期植入。此外，对HLF的异构体特异性解剖揭示了维持HSC自我更新的精确染色质调控。总之，我们描述了一个模型，在这个模型中，HSC功能通过发育程序、专门的微环境和转录调节机制的协调作用而出现。定义人类干细胞的分子语法可能最终使造血干细胞在再生医学和白血病中的合理产生、扩展和治疗操作成为可能。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.