Specific fate decisions in adult hepatic progenitor cells driven by MET and EGFR signaling

Mitsuteru Kitade, Valentina M. Factor, Jesper B. Andersen, Akira Tomokuni, Kosuke Kaji, Hirofumi Akita, Agnes Holczbauer, Daekwan Seo, Jens U. Marquardt, Elizabeth A. Conner, Seung Bum Lee, Yun Han Lee, Snorri S. Thorgeirsson

69 Citations (Scopus)


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 selfrenewal 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 progenitormediated 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.

Original languageEnglish
JournalGenes and Development
Issue number15
Pages (from-to)1706-1717
Number of pages12
Publication statusPublished - 01.08.2013


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