TGF-beta alters liver regeneration and ductular reaction via Notch signaling, thus contributing to HBV-associated fibrogenesis

H. Weng; L. Ciuclan; C. Meyer; T. Huang; P. R. Mertens; M. V. Singer; S. Dooley

doi:10.1055/s-0029-1191753

Zeitschrift für Gastroenterologie, Table of Contents

TGF-beta alters liver regeneration and ductular reaction via Notch signaling, thus contributing to HBV-associated fibrogenesis

H Weng ¹, L Ciuclan ¹, C Meyer ¹, T Huang ², PR Mertens ³, MV Singer ⁴, S Dooley ¹

¹Molekulare Alkoholforschung in der Gastroenterologie; Med. Klinik II; Universitätsmedizin Mannheim; Universität Heidelberg
²Department of Internal Medicine, Zhenhai Lianhua Hospital, Ningbo, China
³Abteilung für Nephrologie und klinischer Immunologie, Universitätsklinikum Aachen, RWTH Aachen
⁴Medizinische Klinik II; Universitätsmedizin Mannheim; Universität Heidelberg

Abstract

Hepatic progenitor cells (HPC) instead of normal hepatocytes become the main population of regenerative hepatocytes, promoting a periportal ductular reaction (DR), which may contribute to periportal fibrogenesis in chronic liver disease in association with HCV and NASH. We hypothesize that a TGF-b-Notch signaling dependent alteration of the replicative pathway of hepatocytes and a subsequent DR play a critical role in HBV associated fibrogenesis and cirrhosis.

105 biopsied liver tissues with chronic HBV infection were stained with cytokeratin-7 (CK7) to quantify DR and the number of HPCs, and with p21 to assess the hepatocyte replicative arrest. CK7 showed a significant correlation with inflammatory grade (r=0.642, P<0.00001), fibrotic stage (r=0.688, P<0.00001) and Smad2-phosphorylation, a marker for running TGF-b signaling (r=0.453, P<0.01). p21 positive hepatocytes were only found in advanced fibrotic and cirrhotic liver tissues, indicating that hepatocyte proliferative arrest is not a premise of HPC activation and DR in HBV-associated liver damage. In CCl₄-damaged Smad7DE1 knock out mice with enhanced TGF-b signaling, p21 staining in hepatocytes was significantly increased when compared to controls. In cultured hepatocytes, TGF-b-induced p21 promoter activation and p21 protein expression were remarkably blunted by g-secretase inhibitor (GSI, a specific Notch inhibitor), indicating that Notch signaling is critical in TGF-b-induced hepatocyte replicative arrest. Finally, we found that treatment with IFN-g, a TGF-b signaling antagonist, in 18 patients with chronic HBV infection remarkably reduced CK7 positive cell number, further supporting involvement of TGF-b in generation of HPCs and the DR in chronic HBV infection.

Conclusion: TGF-b plays a critical role in the altered replicative pathway of hepatocytes via a Notch-dependent pathway in HBV-associated liver damage. TGF-b induces HPC activation and DR, which contribute to HBV-related liver fibrogenesis.

TGF-beta - ductular reaction - hepatic progenic cells - hepatocyte proliferative arrest - portal fibrogenesis