Recapitulation of premature ageing with iPSCs from Hutchinson-Gilford progeria syndrome.
Recapitulation of premature ageing with iPSCs from Hutchinson-Gilford progeria syndrome.
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DOI：
10.1038/nature09879
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发表时间：
2011-04-14
期刊：
影响因子：
64.8
通讯作者：
Izpisua Belmonte, Juan Carlos
中科院分区：
文献类型：
--
作者：
Liu, Guang-Hui;Barkho, Basam Z.;Ruiz, Sergio;Diep, Dinh;Qu, Jing;Yang, Sheng-Lian;Panopoulos, Athanasia D.;Suzuki, Keiichiro;Kurian, Leo;Walsh, Christopher;Thompson, James;Boue, Stephanie;Fung, Ho Lim;Sancho-Martinez, Ignacio;Zhang, Kun;Yates, John, III;Izpisua Belmonte, Juan Carlos
Hutchinson-Gilford progeria syndrome（HGPS）是一种罕见的、致命的人类早衰性疾病，以过早的动脉硬化和血管平滑肌细胞（SMC）变性为特征。HGPS是由核纤层蛋白A（LMNA）基因中的单点突变引起的，导致产生早老蛋白，其是核纤层蛋白A的截短剪接突变体。早老蛋白的积累导致各种与衰老相关的核缺陷，包括核纤层的解体和异染色质的丢失。在这里，我们报告了从HGPS患者获得的成纤维细胞中诱导多能干细胞（iPSC）的产生。HGPS-iPSC显示缺乏早老蛋白，更重要的是，缺乏通常与过早衰老相关的核膜和表观遗传改变。在HGPS-iPSC分化后，早老蛋白及其衰老相关的表型结果得以恢复。具体地，HGPS-iPSC向SMC的定向分化导致与血管老化相关的过早衰老表型的出现。此外，我们的研究确定DNA依赖性蛋白激酶催化亚基（DNAPKcs，也称为PRKDC）作为早老蛋白的下游靶点。核DNAPK全酶的缺乏与过早以及生理老化相关。由于早老蛋白在生理老化过程中也会积累，因此，我们的研究结果提供了一种基于体外iPSC的模型来研究人类过早和生理性血管老化的发病机制。
Hutchinson–Gilford progeria syndrome (HGPS) is a rare and fatal human premature ageing disease,,,,, characterized by premature arteriosclerosis and degeneration of vascular smooth muscle cells (SMCs),,. HGPS is caused by a single point mutation in the lamin A (LMNA) gene, resulting in the generation of progerin, a truncated splicing mutant of lamin A. Accumulation of progerin leads to various ageing-associated nuclear defects including disorganization of nuclear lamina and loss of heterochromatin,,,. Here we report the generation of induced pluripotent stem cells (iPSCs) from fibroblasts obtained from patients with HGPS. HGPS-iPSCs show absence of progerin, and more importantly, lack the nuclear envelope and epigenetic alterations normally associated with premature ageing. Upon differentiation of HGPS-iPSCs, progerin and its ageing-associated phenotypic consequences are restored. Specifically, directed differentiation of HGPS-iPSCs to SMCs leads to the appearance of premature senescence phenotypes associated with vascular ageing. Additionally, our studies identify DNA-dependent protein kinase catalytic subunit (DNAPKcs, also known as PRKDC) as a downstream target of progerin. The absence of nuclear DNAPK holoenzyme correlates with premature as well as physiological ageing. Because progerin also accumulates during physiological ageing,,, our results provide anin vitroiPSC-based model to study the pathogenesis of human premature and physiological vascular ageing.
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影响因子：
46.9
作者：
Deng, Jie;Shoemaker, Robert;Xie, Bin;Gore, Athurva;LeProust, Emily M.;Antosiewicz-Bourget, Jessica;Egli, Dieter;Maherali, Nimet;Park, In-Hyun;Yu, Junying;Daley, George Q.;Eggan, Kevin;Hochedlinger, Konrad;Thomson, James;Wang, Wei;Gao, Yuan;Zhang, Kun
通讯作者：
Zhang, Kun
DOI：
10.1073/pnas.0511133103
发表时间：
2006-02-14
影响因子：
11.1
作者：
McClintock, D;Gordon, LB;Djabali, K
通讯作者：
Djabali, K
影响因子：
3.7
作者：
Candelario, Jose;Borrego, Stacey;Comai, Lucio
通讯作者：
Comai, Lucio
DOI：
10.1161/atvbaha.110.209460
发表时间：
2010-11
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Olive M;Harten I;Mitchell R;Beers JK;Djabali K;Cao K;Erdos MR;Blair C;Funke B;Smoot L;Gerhard-Herman M;Machan JT;Kutys R;Virmani R;Collins FS;Wight TN;Nabel EG;Gordon LB
通讯作者：
Gordon LB
影响因子：
7.7
作者：
Espejel, S;Martín, M;Blasco, MA
通讯作者：
Blasco, MA