Kurosawa Shuhei, Iwama Atsushi
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.
Inflamm Regen. 2020 Nov 5;40(1):29. doi: 10.1186/s41232-020-00138-3.
Hematopoietic stem cells (HSCs) have self-renewal capacity and differentiation potential into all lineages of blood cells throughout the lifetime of an organism. The function of HSCs gradually changes during aging. To date, various stress factors influencing HSC aging have been identified. The increased production of reactive oxygen species and DNA damage responses are causatively attributed to HSC aging. The increased apolarity is a prominent feature of aged HSCs, whereas it is less obvious in young HSCs. The bone marrow (BM) microenvironment niche is a crucial factor for HSC aging. Mesenchymal stem cells show skewed differentiation during aging, which leads to decreased bone formation and increased adipogenesis. The accumulation of adipocytes confers negative effects on hematopoiesis. Loss of sympathetic nerve fibers or adrenoreceptor β3 signaling induces premature HSC and niche aging. Epigenetic regulators such as polycomb group proteins and the sirtuin family of proteins act to prevent premature aging. Targeting these factors, several rejuvenation strategies for aged HSCs have been employed in mice. However, we still do not know whether these strategies can be extrapolated to human HSCs. Aging is frequently accompanied by the development of clonal hematopoiesis, which is called age-related clonal hematopoiesis (ARCH) or clonal hematopoiesis of indeterminate potential (CHIP). Most ARCH/CHIP mutations occur in genes encoding epigenetic regulators including DNMT3A, TET2, and ASXL1, which suggests the relevance of epigenetic drift during the aging process. ARCH/CHIP is a strong risk factor for subsequent hematologic cancer. Notably, it also has an impact on the development of non-malignant disorders such as coronary heart disease. Further studies are warranted to decipher the complete picture of molecular crosstalk that regulates HSC aging.
造血干细胞（HSCs）具有自我更新能力，并在生物体的整个生命周期中具有分化为所有血细胞谱系的潜力。造血干细胞的功能在衰老过程中会逐渐发生变化。迄今为止，已经确定了各种影响造血干细胞衰老的应激因素。活性氧的产生增加和DNA损伤反应被认为是造血干细胞衰老的原因。极性增加是衰老造血干细胞的一个突出特征，而在年轻造血干细胞中则不太明显。骨髓（BM）微环境龛是造血干细胞衰老的关键因素。间充质干细胞在衰老过程中表现出分化偏向，这导致骨形成减少和脂肪生成增加。脂肪细胞的积累对造血产生负面影响。交感神经纤维或肾上腺素能受体β3信号的丧失会诱导造血干细胞和龛的过早衰老。表观遗传调节因子，如多梳蛋白家族和沉默调节蛋白家族的蛋白质，起到防止过早衰老的作用。针对这些因素，已经在小鼠中采用了几种使衰老造血干细胞恢复活力的策略。然而，我们仍然不知道这些策略是否可以推广到人类造血干细胞。衰老常常伴随着克隆性造血的发展，这被称为年龄相关克隆性造血（ARCH）或不确定潜能克隆性造血（CHIP）。大多数ARCH/CHIP突变发生在编码表观遗传调节因子的基因中，包括DNMT3A、TET2和ASXL1，这表明衰老过程中表观遗传漂移的相关性。ARCH/CHIP是后续血液系统癌症的一个强大风险因素。值得注意的是，它也对诸如冠心病等非恶性疾病的发展产生影响。有必要进行进一步的研究，以阐明调节造血干细胞衰老的分子相互作用的全貌。
