Clinical Trials Study
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World J Gastroenterol. Aug 14, 2014; 20(30): 10553-10563
Published online Aug 14, 2014. doi: 10.3748/wjg.v20.i30.10553
Human liver stem/progenitor cells decrease serum bilirubin in hyperbilirubinemic Gunn rat
Cédric Maerckx, Tatiana Tondreau, Silvia Berardis, Jos van Pelt, Mustapha Najimi, Etienne Sokal
Cédric Maerckx, Tatiana Tondreau, Silvia Berardis, Mustapha Najimi, Etienne Sokal, Laboratory of Pediatric Hepatology and Cell Therapy, Université Catholique de Louvain - Institut de Recherche Expérimentale et Clinique (IRCE), 1200 Brussels, Belgium
Jos van Pelt, Katholieke Universiteit Leuven, Hepatologie, 3000 Leuven, Belgium
Author contributions: Maerckx C performed the majority of experiments and wrote the manuscript; van Pelt J contributed reagents/analytic tools and analyzed the data; Tondreau T and Najimi M designed the study; Tondreau T, Najimi M and Sokal E coordinated the study and were also involved in editing the manuscript; Berardis S performed some experiments and revised the manuscript.
Supported by Fonds pour la formation à la recherche dans l’industrie et dans l’agriculture
Correspondence to: Etienne Sokal, MD, Professor of Medicine, Laboratory of Pediatric Hepatology and Cell Therapy, Université Catholique de Louvain - Institut de Recherche Expérimentale et Clinique (IRCE), 52, Avenue Mounier - Tour Vésale +3, 1200 Brussels, Belgium. etienne.sokal@uclouvain.be
Telephone: +32-2-7641387 Fax: +32-2-7648909
Received: December 13, 2013
Revised: February 8, 2014
Accepted: March 8, 2014
Published online: August 14, 2014
Processing time: 248 Days and 16.1 Hours
Abstract

AIM: To test the ability of adult-derived human liver stem/progenitor cells (ADHLSC) from large scale cultures to conjugate bilirubin in vitro and in bilirubin conjugation deficient rat.

METHODS: ADHLSC from large scale cultures were tested for their phenotype and for their capacity to conjugate bilirubin in vitro after hepatogenic differentiation. In vivo, Gunn rats [uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1) deficient animal] were injected with ADHLSC and cryopreserved hepatocytes (positive control). Two, 4, 13 and 27 wk post-transplantation, transplanted Gunn rat bilirubin serum levels were determined by high performance liquid chromatography. Human transplanted cell engraftment was assessed 27 wk post-transplantation using immunohistochemistry and RTqPCR.

RESULTS: Large scale culture conditions do not modify ADHLSC phenotype, ADHLSC were able to specifically conjugate bilirubin. ADHLSC were intraportally injected into Gunn rats and blood UCB was measured at different times post-transplantation, infused-Gunn rats exhibited a metabolic effect 3 mo post-transplantation and maintained over a 6 mo period. ADHLSC engraftment into Gunn rat’s liver was demonstrated by RTqPCR and immunohistochemistry against albumin and UGT1A1.

CONCLUSION: ADHLSC from large scale cultures are efficient in conjugating bilirubin in vitro and in restoring a deficient metabolic function (reducing bilirubin level) in hyperbilirubinemic rats.

Keywords: Liver stem/progenitor cells; Gunn rat; Hepatocyte; in vitro and in situ differentiation; Uridine diphosphate-glucuronosyltransferase 1A1

Core tip: In this study we demonstrated the ability of adult-derived human liver stem/progenitor cells (ADHLSC) to specifically conjugate bilirubin after intraportal injection into Gunn rats a model presenting a deficient bilirubin conjugation function (homologous to human Crigler-Najjar type I syndrome). Infused-Gunn rats exhibited a metabolic effect 3 mo post-transplantation and maintained over a 6 mo period. ADHLSC engraftment into Gunn rat’s liver was demonstrated by immunohistochemistry and RTqPCR. These results suggest the potential of ADHLSC to restore a deficient metabolic function in situ.