martes, 18 de enero de 2011

Modelling the long QT syndrome with induced pluripotent stem cells : Nature : Nature Publishing Group

Modelling the long QT syndrome with induced pluripotent stem cells

* Ilanit Itzhaki,
* Leonid Maizels,
* Irit Huber,
* Limor Zwi-Dantsis,
* Oren Caspi,
* Aaron Winterstern,
* Oren Feldman,
* Amira Gepstein,
* Gil Arbel,
* Haim Hammerman,
* Monther Boulos
* & Lior Gepstein


Affiliations


1. Sohnis Family Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, the Bruce Rappaport Faculty of Medicine, Technion — Israel Institute of Technology, POB 9649, Haifa 31096, Israel
* Ilanit Itzhaki,
* Leonid Maizels,
* Irit Huber,
* Limor Zwi-Dantsis,
* Oren Caspi,
* Aaron Winterstern,
* Oren Feldman,
* Amira Gepstein,
* Gil Arbel &
* Lior Gepstein
2. Department of Cardiology, Rambam Medical Center, the Bruce Rappaport Faculty of Medicine, Technion — Israel Institute of Technology, POB 9649, Haifa 31096, Israel
* Haim Hammerman,
* Monther Boulos &
* Lior Gepstein


Contributions


I.I., L.M., I.H. and L.G. designed the experiments; I.I., L.M., I.H., L.Z.-D., O.C., A.W., O.F., A.G. and G.A performed the experiments; I.I. and L.M. analysed and interpreted the electrophysiological data; M.B. and H.H. performed the clinical assessment; L.G wrote the manuscript; all authors read and approved the manuscript; and L.G. supervised this research work.

Competing financial interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to:

* Lior Gepstein


Journal name: Nature
Year published: (2011)
DOI: doi:10.1038/nature09747

Received
24 June 2010
Accepted
14 December 2010
Published online
16 January 2011


The ability to generate patient-specific human induced pluripotent stem cells (iPSCs)1, 2, 3 offers a new paradigm for modelling human disease and for individualizing drug testing4. Congenital long QT syndrome (LQTS) is a familial arrhythmogenic syndrome characterized by abnormal ion channel function and sudden cardiac death5, 6, 7. Here we report the development of a patient/disease-specific human iPSC line from a patient with type-2 LQTS (which is due to the A614V missense mutation in the KCNH2 gene). The generated iPSCs were coaxed to differentiate into the cardiac lineage. Detailed whole-cell patch-clamp and extracellular multielectrode recordings revealed significant prolongation of the action-potential duration in LQTS human iPSC-derived cardiomyocytes (the characteristic LQTS phenotype) when compared to healthy control cells. Voltage-clamp studies confirmed that this action-potential-duration prolongation stems from a significant reduction of the cardiac potassium current IKr. Importantly, LQTS-derived cells also showed marked arrhythmogenicity, characterized by early-after depolarizations and triggered arrhythmias. We then used the LQTS human iPSC-derived cardiac-tissue model to evaluate the potency of existing and novel pharmacological agents that may either aggravate (potassium-channel blockers) or ameliorate (calcium-channel blockers, KATP-channel openers and late sodium-channel blockers) the disease phenotype. Our study illustrates the ability of human iPSC technology to model the abnormal functional phenotype of an inherited cardiac disorder and to identify potential new therapeutic agents. As such, it represents a promising paradigm to study disease mechanisms, optimize patient care (personalized medicine), and aid in the development of new therapies.
Modelling the long QT syndrome with induced pluripotent stem cells : Nature : Nature Publishing Group




CARDIOLOGÍA
Actualidad Ultimas noticias - JANOes y agencias -
Células madre para estudiar la muerte súbita cardíaca

JANO.es y agencias · 18 Enero 2011 14:00

El nuevo modelo de células madre de un grave trastorno cardíaco, desarrollado por científicos israelís, podría ayudar desarrollar nuevas terapias y medicamentos personalizados.



Investigadores del Instituto de Tecnología de Israel, en Haifa, han desarrollado un nuevo tipo de células madre para el estudio de una grave afección que produce la muerte súbita por ataque cardíaco. Los resultados del estudio se publican en la edición digital de la revista Nature.

Según señalan sus creadores, el nuevo modelo de células madre del trastorno cardíaco grave síndrome de QT largo podría ayudar al desarrollo de nuevas terapias y medicamentos personalizados. Dicho síndrome es una enfermedad rara congénita caracterizada por arritmias cardíacas y muerte súbita cardíaca.

Los investigadores, dirigidos por Lior Gepstein, tomaron células de fibroblasto de un paciente con el síndrome y las utilizaron para generar células madre pluripotentes inducidas. Estas células fueron luego obligadas a convertirse en células de músculo cardíaco, que mostraban patrones anormales de actividad eléctrica característicos del síndrome.

Los autores trataron posteriormente las células con una variedad de fármacos para ver si se aliviaba o agravaba el funcionamiento electrofísico, lo que demuestra el poder de este método para el desarrollo de fármacos y la detección segura específica para cada paciente.


Nature (2011); doi:10.1038/nature09747
Modelling the long QT syndrome with induced pluripotent stem cells : Nature : Nature Publishing Group

Instituto de Tecnología de Israel
Computer Science Department, Technion


Actualidad Ultimas noticias - JANOes y agencias - Celulas madre para estudiar la muerte subita cardiaca - JANO.es - ELSEVIER

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