Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai Minato-ku, Tokyo 108-8639, Japan.
Int J Mol Sci. 2022 Feb 9;23(4):1948. doi: 10.3390/ijms23041948.
Hematopoietic stem cells (HSCs) are the only cell population that possesses both a self-renewing capacity and multipotency, and can give rise to all lineages of blood cells throughout an organism's life. However, the self-renewal capacity of HSCs is not infinite, and cumulative evidence suggests that HSCs alter their function and become less active during organismal aging, leading ultimately to the disruption of hematopoietic homeostasis, such as anemia, perturbed immunity and increased propensity to hematological malignancies. Thus, understanding how HSCs alter their function during aging is a matter of critical importance to prevent or overcome these age-related changes in the blood system. Recent advances in clonal analysis have revealed the functional heterogeneity of murine HSC pools that is established upon development and skewed toward the clonal expansion of functionally poised HSCs during aging. In humans, next-generation sequencing has revealed age-related clonal hematopoiesis that originates from HSC subsets with acquired somatic mutations, and has highlighted it as a significant risk factor for hematological malignancies and cardiovascular diseases. In this review, we summarize the current fate-mapping strategies that are used to track and visualize HSC clonal behavior during development or after stress. We then review the age-related changes in HSCs that can be inherited by daughter cells and act as a cellular memory to form functionally distinct clones. Altogether, we link aging of the hematopoietic system to HSC clonal evolution and discuss how HSC clones with myeloid skewing and low regenerative potential can be expanded during aging.
造血干细胞（HSCs）是唯一具有自我更新能力和多能性的细胞群体，能够在整个生物体的生命过程中产生所有的血细胞谱系。然而，HSCs 的自我更新能力并非无限的，越来越多的证据表明，HSCs 在生物体衰老过程中改变其功能并变得不那么活跃，最终导致造血平衡的破坏，如贫血、免疫失调和增加发生血液系统恶性肿瘤的倾向。因此，了解 HSCs 在衰老过程中如何改变其功能对于预防或克服这些与年龄相关的血液系统变化至关重要。最近在克隆分析方面的进展揭示了小鼠 HSC 池在发育过程中建立的功能异质性，并在衰老过程中偏向于功能稳定的 HSC 的克隆扩增。在人类中，下一代测序揭示了起源于具有获得性体细胞突变的 HSC 亚群的与年龄相关的克隆性造血，并将其突出为血液系统恶性肿瘤和心血管疾病的重要危险因素。在这篇综述中，我们总结了目前用于跟踪和可视化 HSC 克隆行为在发育过程中或应激后变化的命运图谱策略。然后，我们回顾了可以被子细胞继承并作为细胞记忆形成功能不同的克隆的与年龄相关的 HSC 变化。总之，我们将造血系统的衰老与 HSC 克隆进化联系起来，并讨论了在衰老过程中如何扩大具有髓系偏向和低再生潜能的 HSC 克隆。
