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

TY - JOUR

T1 - Specific fate decisions in adult hepatic progenitor cells driven by MET and EGFR signaling

AU - Kitade, Mitsuteru

AU - Factor, Valentina M

AU - Andersen, Jesper Bøje

AU - Tomokuni, Akira

AU - Kaji, Kosuke

AU - Akita, Hirofumi

AU - Holczbauer, Agnes

AU - Seo, Daekwan

AU - Marquardt, Jens U

AU - Conner, Elizabeth A

AU - Lee, Seung-Bum

AU - Lee, Yun-Han

AU - Thorgeirsson, Snorri S

PY - 2013/8/1

Y1 - 2013/8/1

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Differentiation

KW - Cell Line

KW - Cells, Cultured

KW - Hepatocytes

KW - Mice

KW - Mice, SCID

KW - Oncogene Protein v-akt

KW - Receptor, Epidermal Growth Factor

KW - Receptors, Notch

KW - STAT3 Transcription Factor

KW - Signal Transduction

KW - Stem Cells

U2 - 10.1101/gad.214601.113

DO - 10.1101/gad.214601.113

M3 - Journal article

C2 - 23913923

SN - 0890-9369

VL - 27

SP - 1706

EP - 1717

JO - Genes & Development

JF - Genes & Development

IS - 15

ER -