微塑料通过破坏肠道微生物群-次黄嘌呤-Wnt轴抑制造血干细胞的自我更新。

IF 13 1区 生物学 Q1 CELL BIOLOGY Cell Discovery Pub Date : 2024-03-29 DOI:10.1038/s41421-024-00665-0
Lingli Jiang, Yishan Ye, Yingli Han, Qiwei Wang, Huan Lu, Jinxin Li, Wenchang Qian, Xin Zeng, Zhaoru Zhang, Yanmin Zhao, Jimin Shi, Yi Luo, Yunfei Qiu, Jun Sun, Jinghao Sheng, He Huang, Pengxu Qian
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摘要

微塑料(MPs)是全球生物圈中普遍存在的污染物,通过吸入或摄入进入人体,对人类健康构成重大风险。最新研究表明,微塑料存在于骨髓中,会损害造血系统。然而,MPs 对造血干细胞(HSCs)产生影响的具体机制及其在造血干细胞移植(HSCT)中的临床意义在很大程度上仍不明确。在这里,我们建立了一个长期摄入 MPs 的小鼠模型,并发现 MPs 会对造血系统造成严重损害。口服灌胃MPs或粪便移植MPs处理过的小鼠的微生物群明显削弱了造血干细胞的自我更新和重建能力。从机理上讲,MPs 并不直接杀死造血干细胞,而是破坏了肠道结构和通透性,最终改善了肠道中的利剑花科和次黄嘌呤的丰度,并使骨髓造血干细胞中的 HPRT-Wnt 信号失活。此外,在小鼠体内施用利血平或次黄嘌呤以及在培养系统中施用 WNT10A 可显著缓解 MPs 诱导的造血干细胞缺陷。最后,我们在一组接受健康捐献者异基因造血干细胞移植的人类患者中进行了验证,结果发现患者的存活时间与MPs水平呈负相关,而与造血干细胞捐献者粪便和血液中Rikenellaceae和次黄嘌呤的丰度呈正相关。总之,我们的研究揭示了MPs在造血干细胞中的有害作用和机制,为防止MPs对造血干细胞的损伤提供了潜在的策略,也为临床实践中选择合适的造血干细胞移植供体提供了基本的参考。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Microplastics dampen the self-renewal of hematopoietic stem cells by disrupting the gut microbiota-hypoxanthine-Wnt axis.

Microplastics (MPs) are contaminants ubiquitously found in the global biosphere that enter the body through inhalation or ingestion, posing significant risks to human health. Recent studies emerge that MPs are present in the bone marrow and damage the hematopoietic system. However, it remains largely elusive about the specific mechanisms by which MPs affect hematopoietic stem cells (HSCs) and their clinical relevance in HSC transplantation (HSCT). Here, we established a long-term MPs intake mouse model and found that MPs caused severe damage to the hematopoietic system. Oral gavage administration of MPs or fecal transplantation of microbiota from MPs-treated mice markedly undermined the self-renewal and reconstitution capacities of HSCs. Mechanistically, MPs did not directly kill HSCs but disrupted gut structure and permeability, which eventually ameliorated the abundance of Rikenellaceae and hypoxanthine in the intestine and inactivated the HPRT-Wnt signaling in bone marrow HSCs. Furthermore, administration of Rikenellaceae or hypoxanthine in mice as well as treatment of WNT10A in the culture system substantially rescued the MPs-induced HSC defects. Finally, we validated in a cohort of human patients receiving allogenic HSCT from healthy donors, and revealed that the survival time of patients was negatively correlated with levels of MPs, while positively with the abundance of Rikenellaceae, and hypoxanthine in the HSC donors' feces and blood. Overall, our study unleashes the detrimental roles and mechanisms of MPs in HSCs, which provides potential strategies to prevent hematopoietic damage from MPs and serves as a fundamental critique for selecting suitable donors for HSCT in clinical practice.

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来源期刊
Cell Discovery
Cell Discovery Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
24.20
自引率
0.60%
发文量
120
审稿时长
20 weeks
期刊介绍: Cell Discovery is a cutting-edge, open access journal published by Springer Nature in collaboration with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). Our aim is to provide a dynamic and accessible platform for scientists to showcase their exceptional original research. Cell Discovery covers a wide range of topics within the fields of molecular and cell biology. We eagerly publish results of great significance and that are of broad interest to the scientific community. With an international authorship and a focus on basic life sciences, our journal is a valued member of Springer Nature's prestigious Molecular Cell Biology journals. In summary, Cell Discovery offers a fresh approach to scholarly publishing, enabling scientists from around the world to share their exceptional findings in molecular and cell biology.
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