Knockout of Secretin Receptor Reduces Biliary Damage and Liver Fibrosis in Mdr2 Mice by Diminishing Senescence of Cholangiocytes

Overview

Journal Lab Invest

Specialty Pathology

Date 2018 Jul 7

PMID 29977037

Citations 30

Authors

Tianhao Zhou

Nan Wu

Fanyin Meng

Julie Venter

Thao K Giang

Heather Francis

Konstantina Kyritsi

Chaodong Wu

Antonio Franchitto

Domenico Alvaro

Marco Marzioni

Paolo Onori

Romina Mancinelli

Eugenio Gaudio

Shannon Glaser

Gianfranco Alpini

Affiliations

Soon will be listed here.

Abstract

Secretin receptor (SR), only expressed by cholangiocytes, plays a key role in the regulation of biliary damage and liver fibrosis. The aim of this study was to determine the effects of genetic depletion of SR in Mdr2 mice on intrahepatic biliary mass, liver fibrosis, senescence, and angiogenesis. 12 wk SR, Mdr2, and SR/Mdr2 mice with corresponding wild-type mice were used for the in vivo studies. Immunohistochemistry or immunofluorescence was performed in liver sections for (i) biliary expression of SR; (ii) hematoxylin and eosin; (iii) intrahepatic biliary mass by CK-19; (iv) fibrosis by Col1a1 and α-SMA; (v) senescence by SA-β-gal and p16; and (vi) angiogenesis by VEGF-A and CD31. Secretin (Sct) and TGF-β1 levels were measured in serum and cholangiocyte supernatant by ELISA. In total liver, isolated cholangiocytes or HSCs, we evaluated the expression of fibrosis markers (FN-1 and Col1a1); senescence markers (p16 and CCL2); microRNA 125b and angiogenesis markers (VEGF-A, VEGFR-2, CD31, and vWF) by immunoblots and/or qPCR. In vitro, we measured the paracrine effect of cholangiocyte supernatant on the expression of senescent and fibrosis markers in human hepatic stellate cells (HHSteCs). The increased level of ductular reaction, fibrosis, and angiogenesis in Mdr2 mice was reduced in SR/Mdr2 mice. Enhanced senescence levels in cholangiocytes from Mdr2 mice were reversed to normal in SR/Mdr2 mice. However, senescence was decreased in HSCs from Mdr2 mice but returned to normal values in SR/Mdr2 mice. In vitro treatment of HHSteCs with supernatant from cholangiocyte lacking SR (containing lower biliary levels of Sct-dependent TGF-β1) have decreased fibrotic reaction and increased cellular senescence. Sct-induced TGF-β1 secretion was mediated by microRNA 125b. Our data suggest that differential modulation of angiogenesis-dependent senescence of cholangiocytes and HSCs may be important for the treatment of liver fibrosis in cholangiopathies.

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