Mesenchymal Stromal Cell Therapy in Novel Porcine Model of Diffuse Liver Damage Induced by Repeated Biliary Obstruction.

Lucie Vištejnová,Arvind Kumar,Jan Beneš,Ondřej Vyčítal,Milena Králíčková,Petr Hošek,Yaroslav Kolinko,Jaroslav Racek,Jana Křečková,Zbyněk Tonar,Marie Karlíková,Jan Brůha,Daniel Lysák,Václav Liška,Tereza Blassová,Hynek Mírka,Michaela Brychtová

doi:10.3390/ijms22094304

Lucie Vištejnová, Arvind Kumar + Show 15 more

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https://doi.org/10.3390/ijms22094304

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Abstract

In liver surgery, biliary obstruction can lead to secondary biliary cirrhosis, a life-threatening disease with liver transplantation as the only curative treatment option. Mesenchymal stromal cells (MSC) have been shown to improve liver function in both acute and chronic liver disease models. This study evaluated the effect of allogenic MSC transplantation in a large animal model of repeated biliary obstruction followed by partial hepatectomy. MSC transplantation supported the growth of regenerated liver tissue after 14 days (MSC group, n = 10: from 1087 ± 108 (0 h) to 1243 ± 92 mL (14 days); control group, n = 11: from 1080 ± 95 (0 h) to 1100 ± 105 mL (14 days), p = 0.016), with a lower volume fraction of hepatocytes in regenerated liver tissue compared to resected liver tissue (59.5 ± 10.2% vs. 70.2 ± 5.6%, p < 0.05). Volume fraction of connective tissue, blood vessels and bile vessels in regenerated liver tissue, serum levels of liver enzymes (AST, ALT, ALP and GGT) and liver metabolites (albumin, bilirubin, urea and creatinine), as well as plasma levels of IL-6, IL-8, TNF-α and TGF-β, were not affected by MSC transplantation. In our novel, large animal (pig) model of repeated biliary obstruction followed by partial hepatectomy, MSC transplantation promoted growth of liver tissue without any effect on liver function. This study underscores the importance of translating results between small and large animal models as well as the careful translation of results from animal model into human medicine.

Highlights

Introduction distributed under the terms andRepeated or chronic biliary obstruction is a common result of choledocholithiasis, cholangitis or postoperative complications of cholecystectomy
Stem cell phenotype of transplanted Mesenchymal stromal cells (MSC) was evaluated by flow cytometry
The present study employed a novel porcine model of repeated biliary obstruction followed by left lobe resection in order to simulate clinical appearance and intervention of chronic cholestasis that can lead to secondary biliary cirrhosis (SBC)

Summary

Introduction

Repeated or chronic biliary obstruction is a common result of choledocholithiasis, cholangitis or postoperative complications of cholecystectomy. The most severe consequence of chronic cholestasis is secondary biliary cirrhosis (SBC), a life-threatening disease with liver transplantation as the only curative treatment option [2,3,4,5,6]. In cases of SBC, the only curative treatment that exists to control disease spreading and liver failure is liver transplantation [2,4,5]. Liver transplantation has been associated with good long-term outcomes for patients with SBC, increasing 5-year survival rates to 69–75% [4,9,10]. On top of the existing limitations surrounding liver transplantation, additional long-term complications associated with biliary obstruction can hinder surgical efficacy. The high risk of PH in cirrhotic patients can lead to increased secondary bleeding during surgery, and the presence of PH can even increase 60-day postoperative mortality rates for patients undergoing any surgery for bile duct strictures from 2% to 23% [2,3,13,14]

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