Human iPSC-based modeling of late-onset disease via progerin-induced aging.
Human iPSC-based modeling of late-onset disease via progerin-induced aging.
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DOI：
10.1016/j.stem.2013.11.006
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发表时间：
2013-12-05
期刊：
影响因子：
23.9
通讯作者：
Studer L
中科院分区：
文献类型：
--
作者：
Miller JD;Ganat YM;Kishinevsky S;Bowman RL;Liu B;Tu EY;Mandal PK;Vera E;Shim JW;Kriks S;Taldone T;Fusaki N;Tomishima MJ;Krainc D;Milner TA;Rossi DJ;Studer L
将体细胞重编程为诱导多能干细胞（iPSC），将其身份重置回胚胎年龄，因此为晚发型疾病建模提出了一个重大障碍。在这项研究中，我们描述了一种在人类iPSC衍生谱系中诱导衰老相关特征的策略，并将其应用于帕金森病（PD）的建模。我们的方法涉及早老蛋白的表达，早老蛋白是与过早衰老相关的核纤层蛋白A的截短形式。我们发现，早老蛋白在iPSC衍生的成纤维细胞和神经元中的表达诱导了多种衰老相关的标志物和特征，包括多巴胺特异性表型，如神经黑色素积累。PD-iPSC衍生多巴胺神经元的诱导衰老揭示了需要衰老和遗传易感性的疾病表型，例如明显的树突变性、酪氨酸羟化酶（TH）表达的进行性丧失以及线粒体或路易体前体内含物增大。因此，我们的研究表明，早老蛋白诱导的衰老可用于揭示基于hiPSC的疾病模型中迟发性年龄相关疾病的特征。
Reprogramming somatic cells to induced pluripotent stem cells (iPSCs), resets their identity back to an embryonic age, and thus presents a significant hurdle for modeling late-onset disorders. In this study, we describe a strategy for inducing aging-related features in human iPSC-derived lineages and apply it to the modeling of Parkinson’s disease (PD). Our approach involves expression of progerin, a truncated form of lamin A associated with premature aging. We found that expression of progerin in iPSC-derived fibroblasts and neurons induces multiple aging-related markers and characteristics, including dopamine-specific phenotypes such as neuromelanin accumulation. Induced aging in PD-iPSC-derived dopamine neurons revealed disease phenotypes that require both aging and genetic susceptibility, such as pronounced dendrite degeneration, progressive loss of tyrosine-hydroxylase (TH) expression and enlarged mitochondria or Lewy body-precursor inclusions. Thus, our study suggests that progerin-induced aging can be used to reveal late-onset age-related disease features in hiPSC-based disease models.
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影响因子：
64.8
作者：
Kriks, Sonja;Shim, Jae-Won;Piao, Jinghua;Ganat, Yosif M.;Wakeman, Dustin R.;Xie, Zhong;Carrillo-Reid, Luis;Auyeung, Gordon;Antonacci, Chris;Buch, Amanda;Yang, Lichuan;Beal, M. Flint;Surmeier, D. James;Kordower, Jeffrey H.;Tabar, Viviane;Studer, Lorenz
通讯作者：
Studer, Lorenz
全基因组甲基化谱揭示了人类衰老速度的定量观点。
影响因子：
16
作者：
Hannum, Gregory;Guinney, Justin;Zhao, Ling;Zhang, Li;Hughes, Guy;Sadda, SriniVas;Klotzle, Brandy;Bibikova, Marina;Fan, Jian-Bing;Gao, Yuan;Deconde, Rob;Chen, Menzies;Rajapakse, Indika;Friend, Stephen;Ideker, Trey;Zhang, Kang
通讯作者：
Zhang, Kang
影响因子：
64.8
作者：
Liu, Guang-Hui;Qu, Jing;Suzuki, Keiichiro;Nivet, Emmanuel;Li, Mo;Montserrat, Nuria;Yi, Fei;Xu, Xiuling;Ruiz, Sergio;Zhang, Weiqi;Wagner, Ulrich;Kim, Audrey;Ren, Bing;Li, Ying;Goebl, April;Kim, Jessica;Soligalla, Rupa Devi;Dubova, Ilir;Thompson, James;Yates, John, III;Esteban, Concepcion Rodriguez;Sancho-Martinez, Ignacio;Izpisua Belmonte, Juan Carlos
通讯作者：
Izpisua Belmonte, Juan Carlos
影响因子：
2.5
作者：
BERNHARDT, R;MATUS, A
通讯作者：
MATUS, A
影响因子：
7.5
作者：
Freije, Jose M. P.;Lopez-Otin, Carlos
通讯作者：
Lopez-Otin, Carlos