A murine model demonstrating reversal of structural and functional correlates of cirrhosis with progenitor cell transplantation

Mark D Muthiah,Daniel Q Huang,Nur Halisah Jumat,Aileen Wee,Mahesh Choolani,Seng Gee Lim,Jerry Kok Yen Chan,Yock-Young Dan,Lei Zhou

doi:10.1038/s41598-019-51189-7

Abstract

Development of cell transplantation for treating liver cirrhosis hinges critically on the availability of animal models for studying human stem cell transplantation. We report an immune-permissive murine model of liver cirrhosis with full clinical correlates of decompensated liver disease, and allows testing efficacy of stem cell transplantation. Liver cirrhosis was induced in Nod-scid gamma(NSG) mice with oral thioacetamide(TA) and compared to controls over 12 months. 4 month TA treated cirrhotic mice were then transplanted intrasplenically with 2million human fetal liver progenitor cells(HFH) and compared with cirrhotic controls 2 months after transplantation. NSG-TA mice developed shrunken and nodular livers with histological evidence of fibrosis as compared to controls. This was associated with evidence of worsening decompensated liver disease, with jaundice, hypoalbuminemia, coagulopathy, and encephalopathy in NSG-TA mice. Transplantation of HFH resulted in improvement in both fibrosis and markers of decompensated liver disease. We have demonstrated that NSG-TA mice can recapitulate the full clinical picture of structural and functional cirrhosis, both of which can be improved by transplantation of human fetal liver cells. This model serves as a valuable tool for validation of in vivo liver stem cell transplantation and opens up opportunities for studying the mechanism how stem cells reverse fibrosis.

Highlights

Development of cell transplantation for treating liver cirrhosis hinges critically on the availability of animal models for studying human stem cell transplantation
As the final common pathway in almost all chronic liver diseases[1,2], its prevalence is estimated at about 1% worldwide[3] and mortality due to liver cirrhosis is rapidly rising in developed countries[4]
Nodular fibrosis was demonstrable by 6 months, with broad septa seen, corresponding to Laennec 4b

Summary

Introduction

Development of cell transplantation for treating liver cirrhosis hinges critically on the availability of animal models for studying human stem cell transplantation. Current murine models of cirrhosis include common bile duct ligation, or hepatotoxin administration alpha-naphthyl-isothiocyanate (ANIT), allyl alcohol (AA), carbon tetrachloride (CCl4), 3,5-diethoxycarbonyl-1,4 -dihydrocollidine (DDC) and silica[11] These models of chronic liver disease do develop fibrosis and nodularity of the liver but few models develop full blown cirrhosis or clinical complications that recapitulate the full clinical spectrum of decompensated liver disease in human patients. Efficacy for progenitor cell transplantation has been shown in in vivo models such as fumarylacetoacetate hydrolase knockout (FAH), urokinase-type plasminogen activator overexpression (uPA) and AhCre, these models use genetic manipulation to exert extreme levels of survival selection pressures to achieve high degrees of stem cell or progenitor cell repopulation[12,13,14] They do not simulate the clinical complications of a decompensated cirrhotic patient. The relevance of these models to clinical cirrhosis and the real life efficacy of new potential therapies in reversing the complications of cirrhosis are not known

Methods

Results

Conclusion