Telomere shortening and loss of self-renewal in dyskeratosis congenita induced pluripotent stem cells.
Telomere shortening and loss of self-renewal in dyskeratosis congenita induced pluripotent stem cells.
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DOI：
10.1038/nature10084
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发表时间：
2011-05-22
期刊：
影响因子：
64.8
通讯作者：
Artandi, Steven E.
中科院分区：
文献类型：
--
作者：
Batista, Luis F. Z.;Pech, MatthewF.;Zhong, Franklin L.;Nguyen, Ha Nam;Xie, Kathleen T.;Zaug, Arthur J.;Crary, Sharon M.;Choi, Jinkuk;Sebastiano, Vittorio;Cherry, Athena;Giri, Neelam;Wernig, Marius;Alter, Blanche P.;Cech, Thomas R.;Savage, Sharon A.;Pera, Renee A. Reijo;Artandi, Steven E.
将患者来源的诱导多能干细胞（iPSC）分化为诸如神经元、肌肉和肝脏的定向命运是理解人类发育和疾病的关键参数的有力方法。未分化的iPSC本身是否可以用于探测疾病机制尚不确定。先天性角化不良（DC）的特征是血液、肺组织和表皮组织的维持缺陷，并且是由控制端粒稳态的基因突变引起的。短端粒是DC的标志，在小鼠模型中损害组织干细胞功能，表明组织干细胞缺陷是DC病理生理学的基础。在这里，我们表明，即使在未分化状态下，来自DC患者的iPSC也具有每种疾病形式的精确生化缺陷特征，并且iPSC中端粒维持缺陷的程度与临床严重程度相关。在来自TERT（端粒酶逆转录酶）杂合突变患者的iPSC中，端粒酶水平降低50%会使伴随重编程的天然端粒延长变钝。相反，X连锁DC中dyskerin（DKC 1）的突变通过阻断端粒酶组装严重损害端粒酶活性，并在重编程过程中破坏端粒延伸。在由TCAB1突变引起的DC形式的iPSC中，端粒酶催化活性未受干扰，但端粒酶延长端粒的能力被废除，因为端粒酶从Cajal小体错误定位到iPSC内的核仁。DKC 1突变型iPSC的长期培养导致端粒逐渐缩短，最终丧失自我更新能力，这表明DC患者的组织干细胞中也发生了类似的过程。来自DC患者的iPSC中的这些发现揭示了未分化的iPSC准确地概括了人类干细胞疾病的特征，并且可以作为用于靶向治疗剂开发的基于细胞培养的系统。
The differentiation of patient-derived induced pluripotent stem cells (iPSCs) to committed fates such as neurons, muscle and liver is a powerful approach for understanding key parameters of human development and disease. Whether undifferentiated iPSCs themselves can be used to probe disease mechanisms is uncertain. Dyskeratosis congenita (DC) is characterized by defective maintenance of blood, pulmonary tissue, and epidermal tissues and is caused by mutations in genes controlling telomere homeostasis. Short telomeres, a hallmark of DC, impairs tissue stem cell function in mouse models, suggesting that a tissue stem cell defect underlies the pathophysiology of DC. Here, we show that even in the undifferentiated state, iPSCs from DC patients harbor the precise biochemical defects characteristic of each form of the disease and that the magnitude of the telomere maintenance defect in iPSCs correlates with clinical severity. In iPSCs from patients with heterozygous mutations in TERT, the telomerase reverse transcriptase, a 50% reduction in telomerase levels blunts the natural telomere elongation that accompanies reprogramming. In contrast, mutation of dyskerin (DKC1) in X-linked DC severely impairs telomerase activity by blocking telomerase assembly and disrupts telomere elongation during reprogramming. In iPSCs from a form of DC caused by mutations in TCAB1, telomerase catalytic activity is unperturbed, yet the ability of telomerase to lengthen telomeres is abrogated, because telomerase mislocalizes from Cajal bodies to nucleoli within the iPSCs. Extended culture of DKC1-mutant iPSCs leads to progressive telomere shortening and eventual loss of self-renewal, suggesting that a similar process occurs in tissue stem cells in DC patients. These findings in iPSCs from DC patients reveal that undifferentiated iPSCs accurately recapitulate features of a human stem cell disease and may serve as a cell culture-based system for the development of targeted therapeutics.
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影响因子：
64.5
作者：
Soldner F;Hockemeyer D;Beard C;Gao Q;Bell GW;Cook EG;Hargus G;Blak A;Cooper O;Mitalipova M;Isacson O;Jaenisch R
通讯作者：
Jaenisch R
影响因子：
64.5
作者：
Venteicher, Andrew S.;Meng, Zhaojing;Artandi, Steven E.
通讯作者：
Artandi, Steven E.
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3.5
作者：
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通讯作者：
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影响因子：
23.9
作者：
Stadtfeld, Matthias;Maherali, Nimet;Hochedlinger, Konrad
通讯作者：
Hochedlinger, Konrad
影响因子：
4.8
作者：
Deb-Rinker, P;Ly, D;Walker, PR
通讯作者：
Walker, PR