英国牛津大学Paresh Vyas团队近期取得重要工作进展，他们研究提出，突变干细胞在人类克隆造血中的选择性优势与炎症和衰老反应减弱有关。相关研究成果2024年6月24日在线发表于《细胞—干细胞》杂志上。

据介绍，当造血干细胞（HSC）获得突变时，克隆性造血（CH）就会出现，最常见的突变是DNMT3A和TET2基因，通过尚不清楚的机制赋予竞争优势。

为了深入了解CH突变如何实现逐渐的克隆扩增，研究人员在人类CH骨髓（BM）样本上使用了高保真基因分型的单细胞多组学。突变细胞的大多数选择性优势发生在HSC内。DNMT3A和TET2突变克隆在早期祖细胞中进一步扩增，而TET2突变以剂量依赖的方式加速骨髓成熟。与非CH样本的HSC相比，来自CH样本的突变和非突变HSC都富含炎症和衰老转录组特征，揭示了非细胞自主效应。

然而，相对于同一样本中的野生型HSC，DNMT3A和TET2突变HSC的炎症反应减弱。

总之，这一研究数据支持一个模型，即CH克隆是逐渐选择的，因为它们能抵抗炎症和衰老的有害影响。

附：英文原文

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

Author: 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, Debra Beazley, Alex Murison, Alicia G. Aguilar-Navarro, Eugenia Flores-Figueroa, Stephanie G. Dakin, Andrew J. Carr, Claus Nerlov, John E. Dick, Stephanie Z. Xie, Paresh Vyas

Issue&Volume: 2024-06-24

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.

DOI: 10.1016/j.stem.2024.05.010

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(24)00207-8