Loss of TET2 in human hematopoietic stem cells alters the development and function of neutrophils
Loss of TET2 in human hematopoietic stem cells alters the development and function of neutrophils
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DOI：
10.1016/j.stem.2023.05.004
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发表时间：
2023-06-01
期刊：
影响因子：
23.9
通讯作者：
Bonnet, Dominique
中科院分区：
文献类型：
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作者：
Encabo, Hector Huerga;Aramburu, Iker Valle;Bonnet, Dominique
体细胞突变通常发生在造血干细胞（HSC）中。一些突变克隆通过克隆造血（CH）生长并产生突变的免疫后代，从而形成宿主免疫。CH患者无症状，但发生白血病、心血管和肺部炎性疾病以及严重感染的风险增加。利用人类HSC（hHSC）的基因工程和免疫缺陷小鼠的移植，我们描述了CH，TET 2中常见的突变基因如何影响人类中性粒细胞的发育和功能。hHSC中TET 2的缺失通过增加中性粒细胞祖细胞的再生能力并产生低颗粒中性粒细胞而在骨髓和外周组织中产生明显的中性粒细胞异质性。遗传TET 2突变的人中性粒细胞会加剧炎症反应，并具有更多的浓缩染色质，这与紧凑的中性粒细胞胞外陷阱（NET）的产生相关。我们在这里揭示了生理异常，可能会为未来的策略提供信息，以检测TET 2-CH和预防与CH相关的NET介导的病理。
Somatic mutations commonly occur in hematopoietic stem cells (HSCs). Some mutant clones outgrow through clonal hematopoiesis (CH) and produce mutated immune progenies shaping host immunity. Individ-uals with CH are asymptomatic but have an increased risk of developing leukemia, cardiovascular and pulmonary inflammatory diseases, and severe infections. Using genetic engineering of human HSCs (hHSCs) and transplantation in immunodeficient mice, we describe how a commonly mutated gene in CH, TET2, affects human neutrophil development and function. TET2 loss in hHSCs produce a distinct neutrophil het-erogeneity in bone marrow and peripheral tissues by increasing the repopulating capacity of neutrophil progenitors and giving rise to low-granule neutrophils. Human neutrophils that inherited TET2 mutations mount exacerbated inflammatory responses and have more condensed chromatin, which correlates with compact neutrophil extracellular trap (NET) production. We expose here physiological abnormalities that may inform future strategies to detect TET2-CH and prevent NET-mediated pathologies associated with CH.