2045 – ORIGINS OF IMMUNE RESILIENCE: NEONATAL HEMATOPOIETIC STEM CELLS ENCODE LIFELONG IMMUNE COMPETENCE AND HEALTH SPAN

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.2026.105573

Marcel Rommel, Atesh Worthington, Alessandra Rodriguez y Baena, Shally Saini, Bryce Manso, Stephanie Smith-Berdan, Angela Deguzman, David Boyd, E. Camilla Forsberg

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引用次数: 0

Abstract

Durable immune competence is essential for healthy aging and successful hematopoietic stem cell (HSC) therapies. Developmental hematopoiesis is functionally heterogeneous, with distinct HSC subsets shaping lifelong immune architecture. Using the FlkSwitch lineage tracing model, we identified a previously unrecognized population of developmentally restricted HSCs (drHSCs) that do not persist in situ as HSCs in adult bone marrow, yet retain robust reconstitution capacity upon transplantation. This raises a fundamental question: Is HSC persistence intrinsically programmed or shaped by irradiation-induced niche perturbation? To decouple intrinsic HSC programming from irradiation-induced niche effects, we transplanted HSCs across life stages into unconditioned NBSGW mice.

In contrast to the myeloid biased output of neonatal, adult, and aged HSCs, neonatal drHSCs sustained serial, multilineage reconstitution for over a year with durable lymphoid bias. Despite a smaller HSC pool, drHSCs more effectively reconstituted circulating and tissue-resident lymphoid compartments, including B1a cells, marginal zone B cells, and γδ T cells across multiple organs. Enhanced output is functionally reflected by elevated IgM and protection against respiratory influenza infection. By eliminating confounding irradiation effects, the unconditioned model shows that drHSC self-renewal and multilineage reconstitution are intrinsic properties. These features are underpinned by a distinct epigenetic landscape, characterized by dynamic cis-regulatory element accessibility and persistence of the developmental regulator Lin28b, which distinguishes drHSCs from adult and aged HSCs.

Collectively, neonatal HSC programs encode durable immune resilience, redefining developmental heterogeneity as a tractable target for improving health span, immune recovery, and transplantation therapies.

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2045 -免疫弹性的起源：新生儿造血干细胞编码终身免疫能力和健康跨度

持久的免疫能力对于健康衰老和成功的造血干细胞（HSC）治疗至关重要。发育造血在功能上是异质的，不同的HSC亚群塑造了终身免疫结构。使用FlkSwitch谱系追踪模型，我们发现了一种以前未被识别的发育受限hsc （drhsc）群体，它们不能在成人骨髓中作为hsc持续存在，但在移植时仍保持强大的重构能力。这就提出了一个基本问题：HSC的持久性是固有的程序还是由辐射引起的生态位扰动形成的？为了将内在HSC编程与辐照诱导的生态位效应分离，我们将HSC移植到非条件NBSGW小鼠的生命阶段。与新生儿、成人和老年造血干细胞的髓系偏倚输出相反，新生儿drhsc持续连续、多系重建超过一年，并伴有持久的淋巴系偏倚。尽管HSC池较小，但drhsc更有效地重建了循环和组织驻留的淋巴细胞室，包括B1a细胞、边缘区B细胞和γδ T细胞。增强的输出在功能上反映在IgM升高和对呼吸道流感感染的保护上。通过消除混杂辐照效应，非条件模型表明drHSC的自我更新和多系重构是其固有特性。这些特征是由一种独特的表观遗传格局所支撑的，其特征是动态顺式调控元件的可及性和发育调控因子Lin28b的持久性，这将drhsc与成人和老年hsc区分开来。总的来说，新生儿HSC项目编码持久的免疫恢复能力，将发育异质性重新定义为改善健康跨度、免疫恢复和移植治疗的可处理目标。持久的免疫能力对于健康衰老和成功的造血干细胞（HSC）治疗至关重要。发育造血在功能上是异质的，不同的HSC亚群塑造了终身免疫结构。使用FlkSwitch谱系追踪模型，我们发现了一种以前未被识别的发育受限hsc （drhsc）群体，它们不能在成人骨髓中作为hsc持续存在，但在移植时仍保持强大的重构能力。这就提出了一个基本问题：HSC的持久性是固有的程序还是由辐射引起的生态位扰动形成的？为了将内在HSC编程与辐照诱导的生态位效应分离，我们将HSC移植到非条件NBSGW小鼠的生命阶段。与新生儿、成人和老年造血干细胞的髓系偏倚输出相反，新生儿drhsc持续连续、多系重建超过一年，并伴有持久的淋巴系偏倚。尽管HSC池较小，但drhsc更有效地重建了循环和组织驻留的淋巴细胞室，包括B1a细胞、边缘区B细胞和γδ T细胞。增强的输出在功能上反映在IgM升高和对呼吸道流感感染的保护上。通过消除混杂辐照效应，非条件模型表明drHSC的自我更新和多系重构是其固有特性。这些特征是由一种独特的表观遗传格局所支撑的，其特征是动态顺式调控元件的可及性和发育调控因子Lin28b的持久性，这将drhsc与成人和老年hsc区分开来。总的来说，新生儿HSC项目编码持久的免疫恢复能力，将发育异质性重新定义为改善健康跨度、免疫恢复和移植治疗的可处理目标。

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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.