title: MAPK/ERK and Wnt/β-Catenin pathways are synergistically involved in proliferation of Sca-1 positive hepatic progenitor cells.
abstract: Hepatic progenitor cells (HPCs) persist in adulthood and have the potential to play a major role in regenerating diseased liver. However, the signaling pathways that both directly and indirectly regulate HPCs' self-renewal and differentiation remain elusive. Previously, we identified a bipotent, stem cell antigen-1 (Sca-1) positive HPC population from naïve adult liver tissue. In the present study, we aimed to investigate the involvement of various signaling pathways in Sca-1(+) HPC proliferation. Epidermal growth factor (EGF) supplementation shows a significant increase in Sca-1(+) HPC proliferation and colony formation while stimulating phosphorylation of ERK1/2 and activating the induction of Cyclin D1. There were no demonstrable effects of EGF on Akt. The MEK inhibitor, PD0325901, inhibits proliferation and ERK1/2 phosphorylation while also suppressing the expression of Cyclin D1. In addition, activation of either IL-6/STAT3 or Wnt/β-Catenin pathway did not independently support cell proliferation and colony formation of HPCs. The Wnt/β-Catenin pathway can cooperate with EGF to significantly promote HPC colony formation ratio and maintain long-term HPC in vitro. The data indicates that the MAPK/ERK pathway is both essential and critical for HPC proliferation, and the Wnt signaling pathway is not sufficient, while it works synergistically with the MAPK/ERK signaling pathway to promote HPC proliferation.
authors.affiliation: Department of Surgery, University of North Carolina at Chapel Hill, NC, United States.
authors.forename: Caixia
authors.initials: C
authors.lastname: Jin
authors.forename: Lisa
authors.initials: L
authors.lastname: Samuelson
authors.forename: Cai-Bin
authors.initials: CB
authors.lastname: Cui
authors.forename: Yangzhong
authors.initials: Y
authors.lastname: Sun
authors.forename: David A
authors.initials: DA
authors.lastname: Gerber
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000032:analysis / Q000378:metabolism*; D049109:Cell Proliferation; D003114:Colony-Forming Units Assay; D004815:Epidermal Growth Factor / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D008099:Liver / Q000166:cytology* / Q000187:drug effects; D008565:Membrane Proteins / Q000032:analysis / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000950:Antigens, Ly; C473711:Chir 99021; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D011725:Pyridines; D011743:Pyrimidines; D051153:Wnt Proteins; D051176:beta Catenin; D004815:Epidermal Growth Factor; D000071679:Glycogen Synthase Kinase 3 beta; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases