Fecal microbiota transplantation from young mice rejuvenates aged hematopoietic stem cells by suppressing inflammation.
Fecal microbiota transplantation from young mice rejuvenates aged hematopoietic stem cells by suppressing inflammation.
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来自年轻小鼠的粪便微生物群移植通过抑制炎症使衰老的造血干细胞恢复活力
DOI：
10.1182/blood.2022017514
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发表时间：
2023-04-06
期刊：
影响因子：
20.3
通讯作者：
Qian, Pengxu
中科院分区：
文献类型：
--
作者：
Zeng, Xiangjun;Li, Xiaoqing;Li, Xia;Wei, Cong;Shi, Ce;Hu, Kejia;Kong, Delin;Luo, Qian;Xu, Yulin;Shan, Wei;Zhang, Meng;Shi, Jimin;Feng, Jingjing;Han, Yingli;Huang, He;Qian, Pengxu
年轻小鼠的FMT恢复了淋巴细胞分化潜能，提高了老年hsc的数量和移植能力。毛缕草科和色氨酸相关代谢物可改善老年小鼠造血干细胞的表型和重建能力。造血干细胞（HSC）衰老伴随着造血重建功能障碍，包括再生和植入能力丧失、骨髓分化偏倚和造血恶性肿瘤风险升高。肠道微生物群是宿主健康和免疫的关键调节因子，最近有报道称其影响造血。然而，目前解释肠道微生物组对衰老造血的直接影响的经验证据有限。在这项研究中，我们将年轻小鼠的粪便微生物群移植（FMT）到老年小鼠身上，观察到老年受体小鼠淋巴细胞分化明显增加，髓细胞分化明显减少。此外，来自年轻小鼠的FMT使衰老的hsc恢复活力，增强了短期和长期造血再生能力。从机制上讲，单细胞RNA测序揭示了来自年轻小鼠的FMT减轻炎症信号，上调FoxO信号通路，并促进hsc在衰老过程中的淋巴样分化。最后，综合微生物组和代谢组分析发现，FMT重塑了肠道微生物群组成和代谢物景观，毛缕菌科和色氨酸相关代谢物促进了造血功能的恢复和衰老hsc的年轻化。总之，我们的研究强调了肠道微生物群在HSC衰老中的重要作用，并为衰老相关血液疾病的治疗策略提供了见解。目前的模型将“炎症老化”视为老年人造血功能障碍的驱动因素，并且高度寻求恢复造血功能的方法。Zeng及其同事在小鼠模型中研究了用幼年微生物群替代衰老肠道微生物群的效果，显著表明粪便微生物群移植可以减轻炎症，恢复衰老造血干细胞（hsc）的淋巴细胞分化和植入能力。此外，作者表明，特定微生物群的代谢物改善了老年小鼠造血干细胞的重建能力，这对探索如何将这些见解转化为临床可行的治疗方法提出了挑战。
FMT from young mice restored lymphoid differentiative potential and improved the number and engraftment ability of aged HSCs. Lachnospiraceae and tryptophan-associated metabolites could improve both the phenotype and the reconstitution capacity of HSCs in aged mice. Hematopoietic stem cell (HSC) aging is accompanied by hematopoietic reconstitution dysfunction, including loss of regenerative and engraftment ability, myeloid differentiation bias, and elevated risks of hematopoietic malignancies. Gut microbiota, a key regulator of host health and immunity, has recently been reported to affect hematopoiesis. However, there is currently limited empirical evidence explaining the direct impact of gut microbiome on aging hematopoiesis. In this study, we performed fecal microbiota transplantation (FMT) from young mice to aged mice and observed a significant increment in lymphoid differentiation and decrease in myeloid differentiation in aged recipient mice. Furthermore, FMT from young mice rejuvenated aged HSCs with enhanced short-term and long-term hematopoietic repopulation capacity. Mechanistically, single-cell RNA sequencing deciphered that FMT from young mice mitigated inflammatory signals, upregulated the FoxO signaling pathway, and promoted lymphoid differentiation of HSCs during aging. Finally, integrated microbiome and metabolome analyses uncovered that FMT reshaped gut microbiota composition and metabolite landscape, and Lachnospiraceae and tryptophan-associated metabolites promoted the recovery of hematopoiesis and rejuvenated aged HSCs. Together, our study highlights the paramount importance of the gut microbiota in HSC aging and provides insights into therapeutic strategies for aging-related hematologic disorders. Current models view “inflamm-aging” as a driver of hematopoietic dysfunction in older individuals, and methods to rejuvenate hematopoiesis are highly sought. Zeng and colleagues investigated the effect of replacement of the aged intestinal microbiome with juvenile microbiota in murine models, remarkably demonstrating that fecal microbiota transplants reduce inflammation, restoring lymphoid differentiation and engraftment capacity of aged hematopoietic stem cells (HSCs). Further, the authors showed that metabolites of specific microbiota species improved the reconstitution capacity of HSCs in aged mice, challenging the field to explore ways to translate these insights into a clinically feasible therapy.
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