title: Specific fate decisions in adult hepatic progenitor cells driven by MET and EGFR signaling.
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.
authors.affiliation: Laboratory of Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Kitade
authors.forename: Valentina M
authors.initials: VM
authors.lastname: Factor
authors.forename: Jesper B
authors.initials: JB
authors.lastname: Andersen
authors.forename: Akira
authors.initials: A
authors.lastname: Tomokuni
authors.forename: Kosuke
authors.initials: K
authors.lastname: Kaji
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Akita
authors.forename: Agnes
authors.initials: A
authors.lastname: Holczbauer
authors.forename: Daekwan
authors.initials: D
authors.lastname: Seo
authors.forename: Jens U
authors.initials: JU
authors.lastname: Marquardt
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Conner
authors.forename: Seung-Bum
authors.initials: SB
authors.lastname: Lee
authors.forename: Yun-Han
authors.initials: YH
authors.lastname: Lee
authors.forename: Snorri S
authors.initials: SS
authors.lastname: Thorgeirsson
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology* / Q000201:enzymology / Q000502:physiology*; D051379:Mice; D016513:Mice, SCID; D051058:Oncogene Protein v-akt / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology* / Q000201:enzymology / Q000502:physiology*
chemical_list: D051880:Receptors, Notch; D050796:STAT3 Transcription Factor; D066246:ErbB Receptors; D051058:Oncogene Protein v-akt
keywords: EGFR; MET; lineage commitment; liver progenitor cells
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