title: Inhibition of Notch signaling affects hepatic oval cell response in rat model of 2AAF-PH.
abstract: BACKGROUND AND AIMS: Activation of the oval cell compartment occurs in the liver when hepatocytes are functionally compromised and/or unable to divide. Our goal was to investigate the systemic signals responsible for determining the efficiency of oval cell-mediated liver regeneration, focusing on the Notch signaling cascade. METHODS: The established oval cell induction protocol of 2-acetylaminofluorine (2-AAF) implantation followed by 70% surgical resection of the liver (partial hepatectomy, PH) was employed in a rat model. This oval cell induction model was further combined with injections of a γ-secretase inhibitor (GSI XX) to examine the effects of Notch inhibition on oval cell-aided regeneration of the liver. RESULTS: Notch signaling was found to be upregulated at the peak of oval cell induction during 2AAF-PH alone. Treatment with GSI XX led to interruption of the Notch signal, as shown by a decrease in expression of Hes1. While there was a robust oval cell response seen at day 11 post-PH, there was a measurable delay in differentiation when Notch was inhibited. This was confirmed morphologically as well as by immunohistochemistry for the oval cell markers, α-fetoprotein, OV-6, and CK19. The hepatocytes seen at day 22 demonstrated an enhanced hepatocellular mitoinhibition index (p21(Waf1)/Ki67), suggestive of dysregulated proliferation and cell cycle progression. Moreover, these hepatocytes exhibited decreased expression of hepatocyte functional markers, such as cytochrome P450 and glucose-6-phosphatase-α. CONCLUSIONS: Taken together, these results identify the Notch signaling pathway as a potent regulator of differentiation and proliferation in oval cells, which is necessary for functional for repair of the liver by oval cells.
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, Program in stem cell Biology and Regenerative Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA.
authors.forename: Houda
authors.initials: H
authors.lastname: Darwiche
authors.forename: Seh-Hoon
authors.initials: SH
authors.lastname: Oh
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Steiger-Luther
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Williams
authors.forename: Dana G
authors.initials: DG
authors.lastname: Pintilie
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Shupe
authors.forename: Bryon E
authors.initials: BE
authors.lastname: Petersen