title: Brief Report: The Deletion of the Phosphatase Regulator NIPP1 Causes Progenitor Cell Expansion in the Adult Liver.
abstract: The Ppp1r8 gene encodes NIPP1, a nuclear interactor of protein phosphatase PP1. The deletion of NIPP1 is embryonic lethal at the gastrulation stage, which has hampered its functional characterization in adult tissues. Here, we describe the effects of a conditional deletion of NIPP1 in mouse liver epithelial cells. Ppp1r8(-/-) livers developed a ductular reaction, that is, bile-duct hyperplasia with associated fibrosis. The increased proliferation of biliary epithelial cells was at least partially due to an expansion of the progenitor cell compartment that was independent of liver injury. Gene-expression analysis confirmed an upregulation of progenitor cell markers in the liver knockout livers but showed no effect on the expression of liver-injury associated regulators of cholangiocyte differentiation markers. Consistent with an inhibitory effect of NIPP1 on progenitor cell proliferation, Ppp1r8(-/-) livers displayed an increased sensitivity to diet-supplemented 3,5-diethoxycarbonyl-1,4-dihydrocollidine, which also causes bile-duct hyperplasia through progenitor cell expansion. In contrast, the liver knockouts responded normally to injuries (partial hepatectomy, single CCl4 administration) that are restored through proliferation of differentiated parenchymal cells. Our data indicate that NIPP1 does not regulate the proliferation of hepatocytes but is a suppressor of biliary epithelial cell proliferation, including progenitor cells, in the adult liver. Stem Cells 2016;34:2256-2262.
authors.affiliation: Department of Cellular and Molecular Medicine, Laboratory of Biosignaling & Therapeutics, KU Leuven, Belgium.
authors.forename: Shannah
authors.initials: S
authors.lastname: Boens
authors.affiliation: Department of Cellular and Molecular Medicine, Laboratory of Biosignaling & Therapeutics, KU Leuven, Belgium.
authors.forename: Iris
authors.initials: I
authors.lastname: Verbinnen
authors.affiliation: Liver Cell Biology Lab, Vrije Universiteit Brussel, Brussel, Belgium.
authors.forename: Stefaan
authors.initials: S
authors.lastname: Verhulst
authors.affiliation: Department of Cellular and Molecular Medicine, Laboratory of Biosignaling & Therapeutics, KU Leuven, Belgium.
authors.forename: Kathelijne
authors.initials: K
authors.lastname: Szekér
authors.affiliation: Department of Cellular and Molecular Medicine, Laboratory of Biosignaling & Therapeutics, KU Leuven, Belgium.
authors.forename: Monica
authors.initials: M
authors.lastname: Ferreira
authors.affiliation: Department of Development and Regeneration, Organ Systems, KU Leuven, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gevaert
authors.affiliation: Department of Pharmaceutical & Pharmacological Sciences, Laboratory for Cell Metabolism, KU Leuven, Belgium.
authors.forename: Myriam
authors.initials: M
authors.lastname: Baes
authors.affiliation: Department of Imaging & Pathology, Laboratory of Translational Cell & Tissue Research, KU Leuven, Belgium.
authors.forename: Tania
authors.initials: T
authors.lastname: Roskams
authors.affiliation: Liver Cell Biology Lab, Vrije Universiteit Brussel, Brussel, Belgium.
authors.forename: Leo A
authors.initials: LA
authors.lastname: van Grunsven
authors.affiliation: Department of Cellular and Molecular Medicine, Laboratory of Biosignaling & Therapeutics, KU Leuven, Belgium.
authors.forename: Aleyde
authors.initials: A
authors.lastname: Van Eynde
authors.affiliation: Department of Cellular and Molecular Medicine, Laboratory of Biosignaling & Therapeutics, KU Leuven, Belgium.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Bollen
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation; D017353:Gene Deletion; D006965:Hyperplasia; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008099:Liver / Q000166:cytology* / Q000378:metabolism; D018345:Mice, Knockout; D009928:Organ Specificity; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D047908:Intracellular Signaling Peptides and Proteins; C021042:protein phosphatase inhibitor-1
keywords: Bile-duct hyperplasia; Ductular reaction; Liver progenitor cells; NIPP1; Protein phosphatase 1