Induced pluripotent stem cell modeling of multisystemic, hereditary transthyretin amyloidosis.
Induced pluripotent stem cell modeling of multisystemic, hereditary transthyretin amyloidosis.
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DOI：
10.1016/j.stemcr.2013.10.003
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发表时间：
2013
影响因子：
5.9
通讯作者：
Murphy, George J.
中科院分区：
文献类型：
--
作者：
Leung, Amy;Nah, Shirley K.;Reid, Whitney;Ebata, Atsushi;Koch, Clarissa M.;Monti, Stefano;Genereux, Joseph C.;Wiseman, R. Luke;Wolozin, Benjamin;Connors, Lawreen H.;Berk, John L.;Seldin, David C.;Mostoslavsky, Gustavo;Kotton, Darrell N.;Murphy, George J.
Familial transthyretin amyloidosis (ATTR) is an autosomal-dominant protein-folding disorder caused by over 100 distinct mutations in the transthyretin (TTR) gene. In ATTR, protein secreted from the liver aggregates and forms fibrils in target organs, chiefly the heart and peripheral nervous system, highlighting the need for a model capable of recapitulating the multisystem complexity of this clinically variable disease. Here, we describe the directed differentiation of ATTR patient-specific iPSCs into hepatocytes that produce mutant TTR, and the cardiomyocytes and neurons normally targeted in the disease. We demonstrate that iPSC-derived neuronal and cardiac cells display oxidative stress and an increased level of cell death when exposed to mutant TTR produced by the patient-matched iPSC-derived hepatocytes, recapitulating essential aspects of the disease in vitro. Furthermore, small molecule stabilizers of TTR show efficacy in this model, validating this iPSC-based, patient-specific in vitro system as a platform for testing therapeutic strategies. Successful modeling of familial amyloidosis in vitro using iPSC technology Proto-fibril formation leads to cellular damage in two target tissues of amyloidosis iPSCs can be used in the testing of novel therapeutics for protein folding disorders This work involves the modeling of hereditary transthyretin amyloidosis in vitro using iPSC technology. Murphy and colleagues demonstrate that it is possible to model a long-term, complex, multisystem disease using hepatic, cardiac, and neuronal lineages derived from patient-specific stem cells and validate this approach for the testing of therapeutic strategies.
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影响因子：
17.1
作者：
Alhamadsheh MM;Connelly S;Cho A;Reixach N;Powers ET;Pan DW;Wilson IA;Kelly JW;Graef IA
通讯作者：
Graef IA
影响因子：
7.4
作者：
Lim, A;Prokaeva, T;Costello, CE
通讯作者：
Costello, CE
影响因子：
5.1
作者：
ARAKI, S;YI, S;YAMARNURA, K
通讯作者：
YAMARNURA, K
影响因子：
7.4
作者：
Cardoso I;Martins D;Ribeiro T;Merlini G;Saraiva MJ
通讯作者：
Saraiva MJ
影响因子：
5.5
作者：
Ackermann, Elizabeth J.;Guo, Shuling;Monia, Brett P.
通讯作者：
Monia, Brett P.