Cell - Direct Reprogramming of Fibroblasts into Functional Cardiomyocytes by Defined Factors

Direct Reprogramming of Fibroblasts into Functional Cardiomyocytes by Defined Factors

Cell, Volume 142, Issue 3, 375-386, 6 August 2010
Copyright 2010 Elsevier Inc. All rights reserved.
10.1016/j.cell.2010.07.002

Referred to by: Getting to the Heart of the Matter: Dire...

Authors
Masaki Ieda, Ji-Dong Fu, Paul Delgado-Olguin, Vasanth Vedantham, Yohei Hayashi, Benoit G. Bruneau, Deepak SrivastavaSee AffiliationsHint: Rollover Authors and Affiliations Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, San Francisco, CA 94158, USA Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94158, USA Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA Corresponding author Present address: Departments of Cardiology and of Clinical and Molecular Cardiovascular Research, Keio University School of Medicine, Shinanomachi 35, Shinjuku-ku, Tokyo 160-8582, Japan

Highlights
•Gata4/Mef2c/Tbx5 directly reprogram fibroblasts into cardiomyocyte-like cells
•Induced cardiomyocytes (iCMs) have spontaneous contraction and action potentials
•iCMs resemble cardiomyocytes in their global gene expression and epigenetic state
•Transplanted cardiac fibroblasts can be reprogrammed into iCMs in vivo

Summary
The reprogramming of fibroblasts to induced pluripotent stem cells (iPSCs) raises the possibility that a somatic cell could be reprogrammed to an alternative differentiated fate without first becoming a stem/progenitor cell. A large pool of fibroblasts exists in the postnatal heart, yet no single master regulator of direct cardiac reprogramming has been identified. Here, we report that a combination of three developmental transcription factors (i.e., Gata4, Mef2c, and Tbx5) rapidly and efficiently reprogrammed postnatal cardiac or dermal fibroblasts directly into differentiated cardiomyocyte-like cells. Induced cardiomyocytes expressed cardiac-specific markers, had a global gene expression profile similar to cardiomyocytes, and contracted spontaneously. Fibroblasts transplanted into mouse hearts one day after transduction of the three factors also differentiated into cardiomyocyte-like cells. We believe these findings demonstrate that functional cardiomyocytes can be directly reprogrammed from differentiated somatic cells by defined factors. Reprogramming of endogenous or explanted fibroblasts might provide a source of cardiomyocytes for regenerative approaches.

10.1016/j.cell.2010.07.002
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Cell - Direct Reprogramming of Fibroblasts into Functional Cardiomyocytes by Defined Factors



CARDIOLOGÍA
Hallan un nuevo método más eficaz de regenerar las células del miocardio
JANO.es y agencias · 06 Agosto 2010 09:54

La nueva técnica evita la muerte del músculo cardíaco mediante tres moléculas capaces de transformar fibroblastos en cardiomiocitos.

Una investigación llevada a cabo por la Universidad de California, Estados Unidos, ha hallado una nueva manera, más eficaz que las anteriores, de evitar la muerte del músculo cardíaco mediante tres moléculas que pueden ser capaces de transformar fibroblastos en células del miocardio. La investigación ha sido publicada en Cell.

El doctor Deepak Srivastava, uno de los investigadores, explicó que para la realización del estudio se inspiraron en el sistema de regeneración de fibroblastos por medio de células madre pluripotentes (iPS), centrándose en hallar el modo de regenerarlos sin necesidad de las células madre.

La investigación se inició con 14 factores cuyo papel en el desarrollo cardíaco ya era conocido. "Esta combinación mostró pequeños, pero seguros signos de que funcionaban", comentó el científico. Entonces, fueron reduciendo los factores, eliminando uno a uno hasta quedarse con los tres que resultaron ser eficientes para la regeneración.

Un 20% más de regeneración
A diferencia de la reprogramación iPS, con ésta se ha conseguido "regenerar un 20% de fibroblastos en cardiomiocitos", afirmó Srivastava. "Este resultado es bastante superior comparado con la combinación de iPS, que lograba transformar con éxito apenas un 0,1%", subrayó.

Según explicó, la regeneración se produce durante tres días, tras esto, durante varias semanas, las células comienzan a latir al igual que las células cardíacas, mientras van adoptando las características del miocardio de forma gradual.

Cuando los fibroblastos tratados con esta combinación se trasplantan a los corazones, al día siguiente, todavía se pueden diferenciar del músculo cardíaco original, lo que ha animado a los investigadores a pensar que las células situadas en el corazón puede ser reprogramadas sin necesidad de sacarlas fuera.

El modo actual de reparar el músculo cardíaco consiste en la inserción de tres genes que codifican los factores de transcripción en células cardíacas mediante un virus. Strivastava avanzó que el objetivo de sus próximas investigaciones es "poder reemplazar este método usando únicamente moléculas u otras proteínas, colocándolas mediante un stent en el corazón, que dirigiese el crecimiento de un nuevo músculo cardíaco".

Ahora, Strivastava explicó que la investigación se centrará en "la búsqueda de moléculas que puedan mimetizar los efectos de esta nueva combinación y pueda desarrollarse fármacos de regeneración cardíaca".


Cell, Volume 142, Issue 3, 375-386, 6 August 2010; doi: 10.1016/j.cell.2010.07.002
http://www.cell.com/abstract/S0092-8674(10)00771-3

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