Decoding immunocompetence code that can reactivate aged hematopoietic stem cells

解码可重新激活老化造血干细胞的免疫能力代码

• 批准号: 21K16271
• 负责人: HO Pui・Yu
• 金额: $ 2.91万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Early-Career Scientists
• 财政年份: 2021
• 资助国家: 日本
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-21K16271/
• 关键词: Hematopoietic stem cell; Trained immunity; Hematopoietic stem cells; Trained innate immunity; Stem cell stress; Bacterial infection

Recent works show that not only adaptive immunity but also innate immunity is capable of memorizing previously-encountered pathogens to develop trained immunity. Accumulating evidences show that HSCs can develop immune memory after microbial infection, although the underlying mechanism still remains unclear. We have previously found that upon gut inflammation, Bacteroides species, one of gram negative bacteria in the gut, infiltrate into body and activate BM haematopoiesis in which hematopoietic progenitor (HPCs) are directed to gut-associated lymph node and generate anti-inflammatory myeloid cells for tissue repair (Hayashi et al., bioRxiv 2021). Thus, we hypothesize that Bacteroides might be able to epigenetically imprint an innate immune memory on HSCs and their derived innate immune cells that exert stronger immunocompetence. To test our hypothesis, we primarily challenged mice with Bacteroides and performed in vivo sepsis model as secondary challenge. Microbial prestimulation can provide cross-protective effect to improve host survival. To elucidate the underlying mechanism, we establish a novel bioinformatic pipeline to integrate single-cell sequencing data, and identified epigenetic priming in anti-inflammatory, innate immunity- and metabolism-related genes at 1-month post-stimulation. The Bacteroides also induced substantial changes in active histone modification in the primed HSCs. Our data suggest that understanding of formation, maintenance and abrogation of innate immune memory in HSCs might help to enforce immune-competent of aged hemato-immune system.

最近的研究表明，不仅是适应性免疫，先天免疫也能够记忆以前遇到的病原体，从而形成经过训练的免疫。越来越多的证据表明造血干细胞在微生物感染后可以产生免疫记忆，尽管其潜在机制尚不清楚。我们之前发现，在肠道炎症时，肠道中的一种革兰氏阴性菌拟杆菌（Bacteroides）渗入体内并激活BM造血，其中造血祖细胞（HPCs）被引导到肠道相关淋巴结并产生抗炎髓细胞进行组织修复（Hayashi et al., bioRxiv 2021）。因此，我们假设拟杆菌可能能够在造血干细胞及其衍生的具有更强免疫能力的先天免疫细胞上留下先天免疫记忆的表观遗传印记。为了验证我们的假设，我们首先用拟杆菌攻击小鼠，然后进行体内脓毒症模型作为二次攻击。微生物预刺激可发挥交叉保护作用，提高宿主存活率。为了阐明潜在的机制，我们建立了一个新的生物信息学管道来整合单细胞测序数据，并在刺激后1个月确定了抗炎、先天免疫和代谢相关基因的表观遗传启动。拟杆菌也诱导了hsc中活性组蛋白修饰的实质性变化。我们的数据表明，了解造血干细胞中先天免疫记忆的形成、维持和消除可能有助于增强老年血液免疫系统的免疫能力。