Division of Oncology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, United States.
Department of Pediatrics, Washington University School of Medicine, Saint Louis, MO, United States.
Front Immunol. 2021 Oct 19;12:767267. doi: 10.3389/fimmu.2021.767267. eCollection 2021.
Aging is associated with significant changes in hematopoiesis that include a shift from lymphopoiesis to myelopoiesis and an expansion of phenotypic hematopoietic stem cells (HSCs) with impaired self-renewal capacity and myeloid-skewed lineage differentiation. Signals from commensal flora support basal myelopoiesis in young mice; however, their contribution to hematopoietic aging is largely unknown. Here, we characterize hematopoiesis in young and middle-aged mice housed under specific pathogen free (SPF) and germ-free (GF) conditions. The marked shift from lymphopoiesis to myelopoiesis that develops during aging of SPF mice is mostly abrogated in GF mice. Compared with aged SPF mice, there is a marked expansion of B lymphopoiesis in aged GF mice, which is evident at the earliest stages of B cell development. The expansion of phenotypic and functional HSCs that occurs with aging is similar in SPF and GF mice. However, HSCs from young GF mice have increased lymphoid lineage output, and the aging-associated expansion of myeloid-biased HSCs is significantly attenuated in GF mice. Consistent with these data, RNA expression profiling of phenotypic HSCs from aged GF mice show enrichment for non-myeloid biased HSCs. Surprisingly, the RNA expression profiling data also suggest that inflammatory signaling is increased in aged GF HSCs compared with aged SPF HSCs. Collectively, these data suggest that microbiota-related signals suppress B lymphopoiesis at multiple stages of development and contribute to the expansion of myeloid-biased HSCs that occurs with aging.
衰老是与造血发生重大变化相关的，包括从淋巴造血向髓样造血的转变，以及表型造血干细胞（HSCs）的扩增，同时伴有自我更新能力受损和偏向髓系的谱系分化。共生菌群的信号支持幼年小鼠的基础髓样生成；然而，它们对造血衰老的贡献在很大程度上是未知的。在这里，我们描述了在特定病原体自由（SPF）和无菌（GF）条件下饲养的年轻和中年小鼠的造血情况。SPF 小鼠衰老过程中从淋巴造血向髓样造血的明显转变在 GF 小鼠中大部分被消除。与年老的 SPF 小鼠相比，年老的 GF 小鼠中 B 淋巴造血有明显的扩增，在 B 细胞发育的最早阶段就很明显。随着衰老而发生的表型和功能 HSCs 的扩增在 SPF 和 GF 小鼠中相似。然而，年轻的 GF 小鼠的 HSCs 具有增加的淋巴系输出，并且与衰老相关的偏向髓系的 HSCs 扩增在 GF 小鼠中显著减弱。与这些数据一致，来自年老的 GF 小鼠的表型 HSCs 的 RNA 表达谱分析显示非髓系偏向 HSCs 的富集。令人惊讶的是，RNA 表达谱数据还表明，与年老的 SPF HSCs 相比，年老的 GF HSCs 中的炎症信号增加。总的来说，这些数据表明，微生物群相关信号在多个发育阶段抑制 B 淋巴造血，并有助于与衰老相关的偏向髓系的 HSCs 的扩增。
