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La supresión prolongada de Mek1/2 afecta el potencial de desarrollo de las células madre embrionarias

Jiho Choi^1,2,3,4, Aaron J Huebner^1,2,3,4, Kendell Clement^3,4,5

¹Massachusetts General Hospital Department of Molecular Biology, Boston, Massachusetts 02114, USA.

|July 27, 2017

Resumen

El cultivo prolongado de células madre embrionarias de ratón (células ES) en un medio de 2i/L provoca cambios epigenéticos irreversibles, que afectan el potencial de desarrollo. La sustitución de la inhibición de Mek1/ 2 por la inhibición de Src preserva la integridad y la función de las células ES.

Área de la Ciencia:

Biología de las células madre
La epigenética
Biología del desarrollo

Sus antecedentes:

Las células madre embrionarias de ratón ingenuo (CE) cultivadas con dos inhibidores de moléculas pequeñas (2i) y el factor inhibidor de la leucemia (LIF) imitan la masa celular interna (ICM).
El carácter transitorio de la MIC in vivo plantea dudas sobre la estabilidad y la funcionalidad a largo plazo de las células ES ingenuas cultivadas in vitro.

Objetivo del estudio:

Investigar los efectos del cultivo prolongado de células ES ingenuas en su estabilidad epigenética y genómica.
Identificar los mecanismos moleculares subyacentes a estos cambios y explorar estrategias para mantener el potencial de desarrollo de las células ES.

Principales métodos:

Cultivo prolongado de células ES de ratón macho y hembra en condiciones diferentes (2i/L, suero+LIF).
Análisis de modificaciones epigenéticas, integridad genómica y potencial de desarrollo.
Estudios mecanicistas que implican la inhibición de vías de señalización específicas (Mek1/2, Src).

Principales resultados:

El cultivo sostenido de 2i/L en células ES masculinas condujo a alteraciones epigenéticas y genómicas irreversibles, reduciendo el potencial de desarrollo.
Las células ES femeninas en el suero + medio LIF mostraron cambios perjudiciales similares a los de las células ES masculinas en 2i/L.
La inhibición de Mek1/ 2 se identificó como un factor primario de estos efectos negativos, en parte a través de la regulación a la baja de las metiltransferasas del ADN.
La sustitución de los inhibidores Mek1/ 2 por inhibidores Src mantuvo la integridad epigenética y genómica, preservando el potencial de desarrollo.

Conclusiones:

La supresión a corto plazo de Mek1/2 puede establecer un estado similar al ICM en las células ES.
La inhibición prolongada de Mek1/ 2 induce cambios epigenéticos irreversibles, comprometiendo la capacidad de desarrollo de las células ES.
La inhibición del Src ofrece una alternativa potencial para mantener la pluripotencia y el potencial de desarrollo de las células ES durante un cultivo prolongado.

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