Selective advantage of mutant stem cells in human clonal hematopoiesis is associated with attenuated response to inflammation and aging

IF 19.8 1区 医学 Q1 CELL & TISSUE ENGINEERING
Niels Asger Jakobsen, Sven Turkalj, Andy G.X. Zeng, Bilyana Stoilova, Marlen Metzner, Susann Rahmig, Murtaza S. Nagree, Sayyam Shah, Rachel Moore, Batchimeg Usukhbayar, Mirian Angulo Salazar, Grigore-Aristide Gafencu, Alison Kennedy, Simon Newman, Benjamin J.L. Kendrick, Adrian H. Taylor, Rasheed Afinowi-Luitz, Roger Gundle, Bridget Watkins, Kim Wheway, Paresh Vyas
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Abstract

Clonal hematopoiesis (CH) arises when hematopoietic stem cells (HSCs) acquire mutations, most frequently in the DNMT3A and TET2 genes, conferring a competitive advantage through mechanisms that remain unclear. To gain insight into how CH mutations enable gradual clonal expansion, we used single-cell multi-omics with high-fidelity genotyping on human CH bone marrow (BM) samples. Most of the selective advantage of mutant cells occurs within HSCs. DNMT3A- and TET2-mutant clones expand further in early progenitors, while TET2 mutations accelerate myeloid maturation in a dose-dependent manner. Unexpectedly, both mutant and non-mutant HSCs from CH samples are enriched for inflammatory and aging transcriptomic signatures, compared with HSCs from non-CH samples, revealing a non-cell-autonomous effect. However, DNMT3A- and TET2-mutant HSCs have an attenuated inflammatory response relative to wild-type HSCs within the same sample. Our data support a model whereby CH clones are gradually selected because they are resistant to the deleterious impact of inflammation and aging.

Abstract Image

人类克隆造血中突变干细胞的选择性优势与炎症和衰老反应减弱有关
当造血干细胞(HSCs)发生突变(最常见的是 DNMT3A 和 TET2 基因突变)时,就会产生克隆性造血(CH),通过尚不清楚的机制赋予造血干细胞竞争优势。为了深入了解CH基因突变如何使克隆逐渐扩增,我们对人类CH骨髓(BM)样本进行了单细胞多组学和高保真基因分型。突变细胞的大部分选择性优势发生在造血干细胞中。DNMT3A和TET2突变克隆在早期祖细胞中进一步扩增,而TET2突变则以剂量依赖的方式加速髓系成熟。意想不到的是,与来自非CH样本的造血干细胞相比,来自CH样本的突变和非突变造血干细胞都富含炎症和衰老转录组特征,这揭示了一种非细胞自主效应。然而,与同一样本中的野生型造血干细胞相比,DNMT3A 和 TET2 突变型造血干细胞的炎症反应较弱。我们的数据支持这样一种模式:CH 克隆是逐渐被筛选出来的,因为它们能抵抗炎症和衰老的有害影响。
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来源期刊
Cell stem cell
Cell stem cell 生物-细胞生物学
CiteScore
37.10
自引率
2.50%
发文量
151
审稿时长
42 days
期刊介绍: Cell Stem Cell is a comprehensive journal covering the entire spectrum of stem cell biology. It encompasses various topics, including embryonic stem cells, pluripotency, germline stem cells, tissue-specific stem cells, differentiation, epigenetics, genomics, cancer stem cells, stem cell niches, disease models, nuclear transfer technology, bioengineering, drug discovery, in vivo imaging, therapeutic applications, regenerative medicine, clinical insights, research policies, ethical considerations, and technical innovations. The journal welcomes studies from any model system providing insights into stem cell biology, with a focus on human stem cells. It publishes research reports of significant importance, along with review and analysis articles covering diverse aspects of stem cell research.
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