Collapse of telomere homeostasis in hematopoietic cells caused by heterozygous mutations in telomerase genes.
Collapse of telomere homeostasis in hematopoietic cells caused by heterozygous mutations in telomerase genes.
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DOI：
10.1371/journal.pgen.1002696
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Lansdorp PM
中科院分区：
文献类型：
--
作者：
Aubert G;Baerlocher GM;Vulto I;Poon SS;Lansdorp PM
端粒酶活性在人造血干细胞和祖细胞的提取物中很容易检测到，但在体外增殖和体内老化时似乎不能维持端粒长度。我们对835名健康人和60名端粒酶活性降低的人的白细胞进行了流式FISH分析，对端粒长度进行了详细的研究。健康个体在任何年龄段的粒细胞和淋巴细胞中的平均端粒长度都有很大的变化。端粒的平均长度随着年龄的增长而下降，其下降速度在年龄特异性断裂点和细胞类型之间不同。在研究的所有细胞亚群中，观察到白细胞端粒长度之间的性别差异;有趣的是，这种趋势在出生时就已经可以检测到。端粒酶逆转录酶（hTERT）或端粒酶RNA模板（hTERC）基因突变的杂合子携带者显示出惊人的和可比的端粒长度缺陷。此外，这些杂合子个体的非携带者亲属的白细胞端粒长度比预期的要短一些;这种差异对粒细胞来说最为显著。由于部分端粒酶缺乏而不能维持端粒稳态被认为会触发细胞衰老或细胞死亡，最终导致组织衰竭综合征。我们的数据与这些陈述一致，并表明正常个体发生类似过程的可能性随着年龄的增长而增加。我们的工作突出了端粒酶在造血系统中的重要作用，并支持造血细胞中的端粒酶水平虽然限制并不能阻止整体端粒缩短，但对维持端粒随年龄的动态平衡至关重要的观点。人的血细胞都起源于一个共同的前体，造血干细胞。端粒酶是一种负责将端粒重复序列添加到染色体末端的酶，在人类造血干细胞中具有活性，但似乎无法随着年龄的增长保持恒定的端粒长度。我们首先记录了835名健康人从出生到100岁的不同血细胞亚群的端粒长度，以描述端粒随年龄的正常磨损率。研究发现，从出生到一生，女性的血细胞端粒长度略长于男性。然后，我们将这些参考数据与端粒酶活性降低的个体及其直系亲属的相似血细胞亚群中的端粒长度进行了比较。在端粒酶缺陷的个体中发现了显著短的端粒，这与他们的细胞病理学和疾病易感性一致，并且在具有正常端粒酶维持的亲属的细胞中发现了比预期短的端粒。我们的数据可以作为正常和加速老化研究中的血细胞端粒长度的参考。
Telomerase activity is readily detectable in extracts from human hematopoietic stem and progenitor cells, but appears unable to maintain telomere length with proliferation in vitro and with age in vivo. We performed a detailed study of the telomere length by flow FISH analysis in leukocytes from 835 healthy individuals and 60 individuals with reduced telomerase activity. Healthy individuals showed a broad range in average telomere length in granulocytes and lymphocytes at any given age. The average telomere length declined with age at a rate that differed between age-specific breakpoints and between cell types. Gender differences between leukocyte telomere lengths were observed for all cell subsets studied; interestingly, this trend could already be detected at birth. Heterozygous carriers for mutations in either the telomerase reverse transcriptase (hTERT) or the telomerase RNA template (hTERC) gene displayed striking and comparable telomere length deficits. Further, non-carrier relatives of such heterozygous individuals had somewhat shorter leukocyte telomere lengths than expected; this difference was most profound for granulocytes. Failure to maintain telomere homeostasis as a result of partial telomerase deficiency is thought to trigger cell senescence or cell death, eventually causing tissue failure syndromes. Our data are consistent with these statements and suggest that the likelihood of similar processes occurring in normal individuals increases with age. Our work highlights the essential role of telomerase in the hematopoietic system and supports the notion that telomerase levels in hematopoietic cells, while limiting and unable to prevent overall telomere shortening, are nevertheless crucial to maintain telomere homeostasis with age. Human blood cells all originate from a common precursor, the hematopoietic stem cell. Telomerase, the enzyme responsible for adding telomere repeats to chromosome ends, is active in human hematopoietic stem cells but appears unable to maintain a constant telomere length with age. We first document the telomere length of different blood cell subsets from 835 healthy individuals between birth and 100 years, to delineate the normal rate of telomere attrition with age. Telomere lengths of blood cells were found to be slightly longer in women than in men, from birth and throughout life. We then compared this reference data to the telomere length in similar blood cell subsets from individuals with reduced telomerase activity as a result of a mutation in one of the genes encoding telomerase and from their direct relatives. Strikingly short telomeres were found in telomerase-deficient individuals, consistent with their cellular pathology and disease susceptibility, and somewhat shorter telomeres than expected were found in cells of relatives with normal telomerase maintenance. Our data can be used as a reference for blood cell telomere length in studies of normal and accelerated aging.
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DOI：
10.1056/nejmra0903373
发表时间：
2009-12-10
期刊：
The New England journal of medicine
影响因子：
--
作者：
Calado RT;Young NS
通讯作者：
Young NS
影响因子：
8.3
作者：
Benetos, A;Okuda, K;Aviv, A
通讯作者：
Aviv, A
DOI：
10.1073/pnas.95.10.5607
发表时间：
1998-05-12
影响因子：
11.1
作者：
Frenck, RW;Blackburn, EH;Shannon, KM
通讯作者：
Shannon, KM
影响因子：
3.7
作者：
Baerlocher, GM;Lansdorp, PM
通讯作者：
Lansdorp, PM
影响因子：
64.8
作者：
di Fagagna, FD;Reaper, PM;Jackson, SP
通讯作者：
Jackson, SP