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Las mutaciones somáticas aumentan la aptitud clonal hepática y la regeneración en la enfermedad hepática crónica
Min Zhu1, Tianshi Lu2, Yuemeng Jia1
1Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Cell
|April 9, 2019
Resumen
Las mutaciones somáticas en las células hepáticas no cancerosas pueden impulsar la expansión clonal, promoviendo la regeneración del tejido en la enfermedad hepática crónica. Estos cambios genéticos, particularmente en PKD1 y ARID1A, ayudan a la reparación del hígado independientemente del desarrollo del cáncer.
Área de la Ciencia:
- Genética y genómica
- Hepatología
- Biología celular
Sus antecedentes:
- Los tejidos normales acumulan cambios genéticos con la edad.
- El papel de las mutaciones somáticas en la expansión clonal de células no malignas durante las enfermedades degenerativas crónicas sigue sin estar claro.
- La cirrosis implica daño tisular significativo y fibrosis.
Objetivo del estudio:
- Investigar si las mutaciones somáticas promueven la expansión clonal de las células no malignas en la enfermedad hepática crónica.
- Para identificar genes y mutaciones específicas involucradas en este proceso.
- Determinar el impacto funcional de estas mutaciones en la regeneración hepática y la respuesta a la lesión.
Principales métodos:
- Secuenciación de exomas de muestras de hígado de 82 pacientes con cirrosis.
- Secuenciación ultra profunda para identificar mutaciones recurrentes.
- En conjunto en el cribado in vivo CRISPR de 147 genes.
- Eliminación condicional de genes heterocigotos en modelos de ratón.
Principales resultados:
- Paisaje mutacional complejo identificado en la cirrosis, con mutaciones recurrentes en PKD1, PPARGC1B, KMT2D y ARID1A.
- El aumento del número y tamaño de los clones mutantes se correlacionó con el estadio de la fibrosis y el daño tisular.
- Se demostró que la pérdida de Pkd1, Kmt2d y Arid1a promueve la expansión clonal.
- La deleción heterocigótica condicional de estos genes confirió hepatoprotección en modelos de lesiones en ratones.
Conclusiones:
- Las mutaciones somáticas pueden impulsar la expansión clonal de las células hepáticas no malignas.
- Estas mutaciones promueven la regeneración de tejidos, potencialmente independientes de la carcinogénesis.
- Los hallazgos sugieren un nuevo papel para las alteraciones somáticas en los mecanismos de reparación de tejidos.
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