Baerlocher Gabriela M, Roth Alexander, Lansdorp Peter M
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, V5Z 1L3, Canada.
Ann N Y Acad Sci. 2003 May;996:44-8. doi: 10.1111/j.1749-6632.2003.tb03231.x.
Hematopoietic stem cells have an impressive regenerative potential, strikingly illustrated in transplantation experiments using limited number of cells. In mice, serial transplantation experiments suggest that individual hematopoietic cells are capable of extensive self-renewal and that any possible limitations in the replicative potential of individual hematopoietic stem cells are not affecting normal blood cell formation. The situation with human hematopoietic stem cells is less clear. Unlike the situation in the mouse, the telomere length in nucleated human blood cells shows a remarkable decline with age. Furthermore, even partial telomerase deficiency in humans typically results in marrow failure, whereas complete lack of telomerase is tolerated up to several generations in the mouse. The decline in telomere length in human leukocytes with age follows a cubic function and is much higher in lymphocytes than in granulocytes. This finding suggests that, under normal circumstances, telomere loss is more likely to compromise the function of lymphocytes than the function of hematopoietic stem cells. To reconcile differences in telomere biology between man and mice, it has been proposed that telomere shortening evolved as a tumor suppressor mechanism in long-lived species that may not exist in shorter-lived mammals. According to this model, telomeres in human cells are intimately involved in signaling cell cycle progression and cell division. Most likely, a minimum number of telomere repeats is required at each telomere to prevent activation of a "telomere checkpoint" and allow cell cycle progression. Telomere length measurements appear useful to distinguish between depletion and exhaustion of hematopoietic stem cells as a cause of marrow failure.
造血干细胞具有令人瞩目的再生潜力，这在使用有限数量细胞的移植实验中得到了显著体现。在小鼠中，连续移植实验表明单个造血细胞能够进行广泛的自我更新，并且单个造血干细胞复制潜力的任何可能限制都不会影响正常血细胞的形成。人类造血干细胞的情况则不太明确。与小鼠不同，有核人类血细胞中的端粒长度随年龄增长显著下降。此外，人类即使部分端粒酶缺乏通常也会导致骨髓衰竭，而在小鼠中完全缺乏端粒酶在几代之内都能耐受。人类白细胞中端粒长度随年龄的下降呈三次函数关系，在淋巴细胞中比在粒细胞中下降得更高。这一发现表明，在正常情况下，端粒丢失更有可能损害淋巴细胞的功能而非造血干细胞的功能。为了协调人类和小鼠端粒生物学的差异，有人提出端粒缩短作为一种肿瘤抑制机制在长寿物种中进化而来，而在寿命较短的哺乳动物中可能不存在。根据这一模型，人类细胞中的端粒密切参与信号传导细胞周期进程和细胞分裂。很可能每个端粒需要最少数量的端粒重复序列来防止“端粒检查点”的激活并允许细胞周期进程。端粒长度测量似乎有助于区分作为骨髓衰竭原因的造血干细胞耗竭和衰竭。
