Do hematopoietic stem cells get old?
Do hematopoietic stem cells get old?
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DOI：
10.1038/leu.2016.301
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发表时间：
2017-03
期刊：
影响因子：
11.4
通讯作者：
Johannes Jung;S. Buisman;G. D. Haan
中科院分区：
文献类型：
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作者：
Johannes Jung;S. Buisman;G. D. Haan
在世界上许多国家，老年人的比例将在未来几十年大幅上升。因此，患有与年龄有关的疾病的患者数量也将增加。这与神经退行性疾病有关，如阿尔茨海默病，许多人会立即将其与老龄化社会联系起来，但它也包括多种血液学综合征，随着年龄的增长，发病率明显增加（图1）。在美国，很长一段时间以来，导致死亡的主要原因一直是心脏病，但最近被癌症所取代。1更多的老年人将导致更多的白血病患者，并增加其治疗的医疗保健费用（图2）。除了这些明确的血液系统疾病外，还有多种其他（前）临床表现可能受到造血系统功能障碍的影响。这些包括，例如，对感染的易感性增加（由于淋巴细胞数量和功能减少），疫苗接种效率降低3和动脉硬化风险增加（由于巨噬细胞活性改变），贫血4，甚至可能是一些神经系统疾病（由于小胶质细胞功能丧失）。为了探索为什么许多血液学疾病在老年人中发生得更频繁，我们首先需要评估血液（前体）细胞随年龄的变化。从功能上讲，随着年龄的增长，造血干细胞产生的后代越来越少。这在老鼠身上得到了最好的研究。虽然年老小鼠的干细胞并不会耗尽，而且经典的连续移植研究也证实了造血干细胞可以比原始供体小鼠活得更久，但也有许多年龄依赖性的有害干细胞表型被报道。最值得注意的是，与年轻细胞相比，当供体细胞来自老年小鼠时，单个或少量纯化的造血干细胞移植的植入水平要低得多。这些数据有力地表明，每个干细胞产生的成熟细胞数量随着年龄的增长而下降。然而，不仅成熟细胞的绝对数量在下降，衰老还与谱系偏斜有关，谱系偏斜指的是观察到骨髓细胞和淋巴细胞的相对比例发生有利于骨髓细胞生成的变化。成熟的、完全分化的血细胞，如红细胞、血小板、粒细胞和巨噬细胞，在正常衰老过程中功能活性降低到什么程度，目前还没有得到很好的研究。
In many countries of the world, the proportion of elderly people will rise very substantially in the upcoming decades. As a result, the number of patients that present with age-related diseases will also increase. This relates to neurodegenerative conditions, such as Alzheimer's disease, that many people will instantly link to an aging society, but it also includes multiple hematological syndromes that display clear increases in incidence with advanced age (Figure 1). Whereas in the United States for a long time, the leading cause of death has been heart disease, this was recently replaced by cancer. 1 More old people will result in more patients with leukemia and in increasing health care costs for their treatment (Figure 2).In addition to these clear-cut hematological diseases, there are multiple other (pre-) clinical manifestations that may be affected by malfunctioning of the hematopoietic system. These include, for example, an increased susceptibility to infections (due to reduced numbers and functioning of lymphocytes), 2 reduced vaccination efficiency 3 and an increased risk of arteriosclerosis (due to altered macrophage activity), anemia 4 and may be even some neurological conditions (as a result of loss of microglia functioning). 5 To explore why many hematological diseases occur much more frequently in older people, we first need to assess what changes with age in blood (precursor) cells. Functionally, hematopoietic stem cells produce fewer progeny as they age. This has been best studied in mice. Although it is clear that old mice do not run out of stem cells, and indeed classical serial transplantation studies have documented that hematopoietic stem cells can outlive their original donor mouse, 6 many age-dependent detrimental stem cell phenotypes have been reported. Most notably, the levels of engraftment upon transplantation of a single or a low number of purified hematopoietic stem cells are much lower when the donor cells originate from an old mouse, compared to young cells. 7 These data strongly suggest that the number of mature cells produced per stem cell declines with age. However, it is not only the absolute number of mature produced cells that is declining, aging is also associated with lineage-skewing, which refers to the observation that the relative proportion myeloid and lymphoid cells changes in favor of myeloid cell production. 8 It has not been very well studied to what extent the functional activity of mature, fully differentiated, blood cells, such as erythrocytes, platelets, granulocytes and macrophages, is reduced upon normal aging.