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Specific fate decisions in adult hepatic progenitor cells driven by MET and EGFR signaling.
Kitade, Mitsuteru; Factor, Valentina M; Andersen, Jesper B; Tomokuni, Akira; Kaji, Kosuke; Akita, Hirofumi; Holczbauer, Agnes; Seo, Daekwan; Marquardt, Jens U; Conner, Elizabeth A; Lee, Seung-Bum; Lee, Yun-Han; Thorgeirsson, Snorri S.
Afiliación
  • Kitade M; Laboratory of Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Genes Dev ; 27(15): 1706-17, 2013 Aug 01.
Article en En | MEDLINE | ID: mdl-23913923
ABSTRACT
The relative contribution of hepatocyte growth factor (HGF)/MET and epidermal growth factor (EGF)/EGF receptor (EGFR), two key signal transduction systems in the normal and diseased liver, to fate decisions of adult hepatic progenitor cells (HPCs) has not been resolved. Here, we developed a robust culture system that permitted expansion and genetic manipulation of cells capable of multilineage differentiation in vitro and in vivo to examine the individual roles of HGF/MET and EGF/EGFR in HPC self-renewal and binary cell fate decision. By employing loss-of-function and rescue experiments in vitro, we showed that both receptors collaborate to increase the self-renewal of HPCs through activation of the extracellular signal-regulated kinase (ERK) pathway. MET was a strong inducer of hepatocyte differentiation by activating AKT and signal transducer and activator of transcription (STAT3). Conversely, EGFR selectively induced NOTCH1 to promote cholangiocyte specification and branching morphogenesis while concomitantly suppressing hepatocyte commitment. Furthermore, unlike the deleterious effects of MET deletion, the liver-specific conditional loss of Egfr facilitated rather than suppressed progenitor-mediated liver regeneration by switching progenitor cell differentiation toward hepatocyte lineage. These data provide new insight into the mechanisms regulating the stemness properties of adult HPCs and reveal a previously unrecognized link between EGFR and NOTCH1 in directing cholangiocyte differentiation.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Células Madre / Transducción de Señal / Diferenciación Celular / Hepatocitos / Receptores ErbB Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Genes Dev Asunto de la revista: BIOLOGIA MOLECULAR Año: 2013 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Células Madre / Transducción de Señal / Diferenciación Celular / Hepatocitos / Receptores ErbB Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Genes Dev Asunto de la revista: BIOLOGIA MOLECULAR Año: 2013 Tipo del documento: Article País de afiliación: Estados Unidos