Inhibition of Notch signaling affects hepatic oval cell response in rat model of 2AAF-PH

Houda Darwiche, Seh-Hoon Oh, Nicole C Steiger-Luther, Jennifer M Williams, Dana G Pintilie, Thomas D Shupe, Bryon E PetersenDepartment of Pathology, Immunology, and Laboratory Medicine, Program in Stem Cell Biology and Regenerative Medicine, College of Medicine, University of Florida, Gainesville, F...

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Autores principales:	Darwiche H, Oh S-H, Steiger-Luther NC, Williams JM, Pintilie DG, Shupe TD, Petersen BE
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2011
Materias:	Diseases of the digestive system. Gastroenterology RC799-869
Acceso en línea:	https://doaj.org/article/758ca23edbb9497f9eeac4b5bfaf06f0
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spelling	oai:doaj.org-article:758ca23edbb9497f9eeac4b5bfaf06f02021-12-02T01:09:00ZInhibition of Notch signaling affects hepatic oval cell response in rat model of 2AAF-PH1179-1535https://doaj.org/article/758ca23edbb9497f9eeac4b5bfaf06f02011-09-01T00:00:00Zhttp://www.dovepress.com/inhibition-of-notch-signaling-affects-hepatic-oval-cell-response-in-ra-a8197https://doaj.org/toc/1179-1535Houda Darwiche, Seh-Hoon Oh, Nicole C Steiger-Luther, Jennifer M Williams, Dana G Pintilie, Thomas D Shupe, Bryon E PetersenDepartment of Pathology, Immunology, and Laboratory Medicine, Program in Stem Cell Biology and Regenerative Medicine, College of Medicine, University of Florida, Gainesville, FL, USABackground 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 &gamma;-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, &alpha;-fetoprotein, OV-6, and CK19. The hepatocytes seen at day 22 demonstrated an enhanced hepatocellular mitoinhibition index (p21Waf1/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-&alpha;.Conclusion: 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 repair of the liver by oval cells.Keywords: Notch, oval cells, liver, regeneration, differentiationDarwiche HOh S-HSteiger-Luther NCWilliams JMPintilie DGShupe TDPetersen BEDove Medical PressarticleDiseases of the digestive system. GastroenterologyRC799-869ENHepatic Medicine: Evidence and Research, Vol 2011, Iss default, Pp 89-98 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Diseases of the digestive system. Gastroenterology RC799-869
spellingShingle	Diseases of the digestive system. Gastroenterology RC799-869 Darwiche H Oh S-H Steiger-Luther NC Williams JM Pintilie DG Shupe TD Petersen BE Inhibition of Notch signaling affects hepatic oval cell response in rat model of 2AAF-PH
description	Houda Darwiche, Seh-Hoon Oh, Nicole C Steiger-Luther, Jennifer M Williams, Dana G Pintilie, Thomas D Shupe, Bryon E PetersenDepartment of Pathology, Immunology, and Laboratory Medicine, Program in Stem Cell Biology and Regenerative Medicine, College of Medicine, University of Florida, Gainesville, FL, USABackground 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 &gamma;-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, &alpha;-fetoprotein, OV-6, and CK19. The hepatocytes seen at day 22 demonstrated an enhanced hepatocellular mitoinhibition index (p21Waf1/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-&alpha;.Conclusion: 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 repair of the liver by oval cells.Keywords: Notch, oval cells, liver, regeneration, differentiation
format	article
author	Darwiche H Oh S-H Steiger-Luther NC Williams JM Pintilie DG Shupe TD Petersen BE
author_facet	Darwiche H Oh S-H Steiger-Luther NC Williams JM Pintilie DG Shupe TD Petersen BE
author_sort	Darwiche H
title	Inhibition of Notch signaling affects hepatic oval cell response in rat model of 2AAF-PH
title_short	Inhibition of Notch signaling affects hepatic oval cell response in rat model of 2AAF-PH
title_full	Inhibition of Notch signaling affects hepatic oval cell response in rat model of 2AAF-PH
title_fullStr	Inhibition of Notch signaling affects hepatic oval cell response in rat model of 2AAF-PH
title_full_unstemmed	Inhibition of Notch signaling affects hepatic oval cell response in rat model of 2AAF-PH
title_sort	inhibition of notch signaling affects hepatic oval cell response in rat model of 2aaf-ph
publisher	Dove Medical Press
publishDate	2011
url	https://doaj.org/article/758ca23edbb9497f9eeac4b5bfaf06f0
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Inhibition of Notch signaling affects hepatic oval cell response in rat model of 2AAF-PH

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