Descripción del proyecto
Mecanismos de regeneración de las células hepáticas
Las células epiteliales hepáticas poseen una plasticidad única por la cual las células terminalmente diferenciadas cambian de identidad para regenerar tejido lesionado o mal desarrollado. En el síndrome de Alagille, algunos pacientes pueden recuperar los conductos biliares hepáticos subdesarrollados, importantes para el drenaje de la bilis. Varios modelos animales del síndrome de Alagille han demostrado que hay diferentes tipos celulares que pueden contribuir a la regeneración de los conductos biliares, que varían en calidad según la región del hígado. El proyecto PlasticLiver empleará un novedoso enfoque de rastreo de linaje de código de barras de alta resolución y perfil de expresión génica para resolver fuentes y mecanismos celulares específicos de la región en la regeneración hepática en un modelo murino para el síndrome de Alagille, contribuyendo a una comprensión más profunda de los programas regenerativos endógenos. Además, el proyecto explorará las posibilidades de mejorar la calidad de la regeneración de las vías biliares.
Objetivo
The liver can regenerate thanks to a unique cell plasticity in which “terminally differentiated cells” change identity. Hepatocytes, the most abundant cell type sustaining liver metabolism, can transdifferentiate into a completely different cell type to repair the bile duct epithelium, which entails not only a fate switch but also a conversion of epithelial polarity. Despite this regenerative capacity, bile duct diseases present a major clinical challenge, often requiring a liver transplant. Activating and controlling endogenous regenerative programs, which preliminary data suggest are liver region-specific, is thus a promising therapeutic strategy but requires a deeper understanding of the underlying mechanisms.
Based on regional differences in the quality of regenerated bile ducts in a mouse model of Alagille syndrome, I hypothesize that bile ducts in the hilar region regenerate via cholangiocyte proliferation, yielding well-formed epithelia, while bile ducts at the organ periphery develop de novo via hepatocyte transdifferentiation, yielding malformed bile ducts with aberrant polarity. Because there are multiple cell sources for liver repair, PlasticLiver aims to account for spatial and within-cell type heterogeneity in the liver during bile duct regeneration. Taking advantage of a novel cutting-edge approach for high resolution barcode lineage tracing and gene expression profiling co-developed in my host lab, I will resolve region-specific cell sources and mechanisms in developing and regenerating livers of a mouse model of Alagille syndrome. Moreover, combining generated single cell gene expression data and microscopy analysis of healthy and regenerated tissues, I will identify molecular mechanisms and potential targets to improve epithelial polarity in regenerated peripheral bile ducts. Ultimately, PlasticLiver will yield fundamental mechanistic insights into cell fate decisions and why liver, but no other organs, uses this type of cellular plasticity.
Ámbito científico
Palabras clave
Programa(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Régimen de financiación
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinador
17177 Stockholm
Suecia