Regenerative medicine has the potential to heal or replace tissues and organs damaged by disease, trauma or age, as well as to normalise congenital defects.

It could bypass the obstacles of liver transplantation, the current therapy used to treat liver failure, which suffers from a shortage of donor organs and often causes serious complications.

  • A clearer understanding of the factors that influence liver regeneration and a more refined ability to predict liver regeneration/healing potential, either before liver resection/embolization or in the context of severe hepatitis, are highly relevant clinical challenges. Furthermore, in vitro models of normal and pathological liver tissue are mandatory to unravel, define and confirm the pathophysiological mechanisms responsible for liver diseases at the molecular level and to improve the efficacy of drug design/validation processes by using relevant human cell models.
  • In patients, multiple compartments (tissues and fluids) will be explored before and after liver surgery (clinical and biological evaluation; hepatic functional imaging). The results of omic approaches, and volumetric/innovative imaging strategies, as well as ChIP-seq (Chromatin ImmunoPrecipitation Sequencing) epigenetic studies of activating and silencing marks, will be combined to construct this predictive overview, with particular focus on bile acids profile.
  • In parallel, bioengineered organoids will be produced:

    (i) to model the liver diseases under study,
    (ii) for predictive toxicology studies and
    (iii) for therapeutic purposes and trials that will be performed, framed by an ethical discussion.

    To exploit this clinical and experimental research, in silico models building upon imaging at the histological and organ levels, dynamic imaging, in vitro models, preclinical studies, and the mathematical modelling of interaction networks, will be implemented to set up predictive tools for post-surgical outcomes, responses to treatment, the healing of hepatitis and the toxic and side effects of new drug candidates.

The goals

Construction of a predictive panel of biomarkers for liver regeneration in different situations: severe hepatitis, major hepatectomy, portal embolization, living donor transplantation.

Production of liver organoids, using human primary or hiPSC-derived hepatocytes and hepatic cells or human cell lines.

These organoids will make it possible the in vitro modelling of liver disorders and the development of complex in vitro models, including micro-fluidised organ-on-a-chip. The relevant parameters will be used to evaluate organoids, as potential readouts of cell/tissue differentiation/function and/or proliferation. In particular, the formation of bile canaliculi within liver organoids will be focused on.

Development of preclinical trials using encapsulated cells and organoids in mice with extended hepatectomies, liver toxicity or biliary cirrhosis as a liver failure model.

In silico modelling of liver disorders and organoid models.

The biomarker study and imaging approach performed in patients and organoids will be used for the in silico modelling of liver tissue structure and functions in the context of:

(i) regeneration after hepatectomy;
(ii) fibrotic liver and corresponding organoid models;
(iii) in vitro models for predictive toxicity;
(iv) clinical trials on cell therapy.

Computational models will assess the consistency of the data collected and help their interpretation at all levels. Bioinformatics analysis will reveal genes acquiring a specific epigenetic signature.

Phase I extracorporeal liver clinical trials

Abio-artificial extracorporeal system hosting encapsulated liver organoids, currently in preclinical trials, will enter in phase I clinical trial at the CHB.

A versatile microfluidic tool for the 3D culture of HepaRG cells seeded at various stages of differentiation.
Boul M, Benzoubir N, Messina A, Ghasemi R, Mosbah IB, Duclos-Vallée JC, Dubart-Kupperschmitt A, Le Pioufle B.
Sci Rep. 2021 Jul 7;11(1):14075. doi: 10.1038/s41598-021-92011-7. PMID: 34234159; PMCID: PMC8263583.
Advanced Techniques and Awaited Clinical Applications for Human Pluripotent Stem Cell Differentiation into Hepatocytes.
Luce E, Messina A, Duclos-Vallée JC, Dubart-Kupperschmitt A.
Hepatology. 2021 Aug;74(2):1101-1116. doi: 10.1002/hep.31705. Epub 2021 Aug 22. PMID: 33420753; PMCID: PMC8457237.
Les organoïdes hépatiques - Quels sont les enjeux ? [Hepatic organoids: What are the challenges?].
Luce E, Messina A, Caillaud A, Si-Tayeb K, Cariou B, Bur E, Dubart-Kupperschmitt A, Duclos-Vallée JC.
Med Sci (Paris). 2021 Oct;37(10):902-909. French. doi: 10.1051/medsci/2021119. Epub 2021 Oct 14. PMID: 34647879.
In vitro recovery of FIX clotting activity as a marker of highly functional hepatocytes in a hemophilia B iPSC model.
Luce E, Steichen C, Allouche M, Messina A, Heslan JM, Lambert T, Weber A, Nguyen TH, Christophe O, Dubart-Kupperschmitt A.
Hepatology. 2021 Oct 23. doi: 10.1002/hep.32211. Epub ahead of print. PMID: 34687060.
Preclinical characterization of alginate-poly-L-lysine encapsulated HepaRG for extracorporeal liver supply.
Pasqua M, Pereira U, de Lartigue C, Nicolas J, Vigneron P, Dermigny Q, Legallais C.
BiotechnolBioeng. 2021 Jan;118(1):453-464. doi: 10.1002/bit.27583. Epub 2020 Oct 9. PMID: 32997339.
Self-Organogenesis from 2D Micropatterns to 3D Biomimetic Biliary Trees.
Gontran E, Loarca L, El Kassis C, Bouzhir L, Ayollo D, Mazari-Arrighi E, Fuchs A, Dupuis-Williams P.
Bioengineering (Basel). 2021 Aug 5;8(8):112. doi: 10.3390/bioengineering8080112. PMID: 34436115; PMCID: PMC8389215.

Genomic integrity of human induced pluripotent stem cells: Reprogramming, differentiation and applications.
Steichen C, Hannoun Z, Luce E, Hauet T, Dubart-Kupperschmitt A.
World J Stem Cells. 2019 Oct 26;11(10):729-747.
doi: 10.4252/wjsc.v11.i10.729. PMID: 31692979
HepaRG Self-Assembled Spheroids in Alginate Beads Meet the Clinical Needs for Bioartificial Liver.
Pasqua M, Pereira U, Messina A, de Lartigue C, Vigneron P, Dubart-Kupperschmitt A, Legallais C. Tissue
Eng Part A. 2020 Jun;26(11-12):613-622. doi:
10.1089/ten.TEA.2019.0262. Epub 2020 Feb 12. PMID: 31914890
iPSCs for modeling familial hypercholesterolemia type II A.
Caron J, Dubart-Kupperschmitt A, Weber A.
Chapter 10 In Advances in Stem Cell Biology,
Recent Advances in iPSC Disease Modeling, Volume 1, 2020, Pages 201-219,
Editor(s): Alexander Birbrair, Academic Press, ISBN 9780128222270,
https://doi.org/10.1016/B978-0-12-822227-0.00010-7.
Liver Regeneration and Recanalization Time Course following Repeated Reversible Portal Vein Embolization in Swine.
Gaillard M, Hornez E, Lecuelle B, Lilin T, Dubart-Kupperschmitt A, Dagher I, Tranchart H. Eur Surg Res.
2020;61(2-3):62-71.
doi: 10.1159/000509713. Epub 2020 Oct 13. PMID: 33049754
Pluripotent stem cell-derived cholangiocytes and cholangiocyte organoids.
Luce E, Dubart-Kupperschmitt A.
Methods Cell Biol. 2020;159:69-93. doi: 10.1016/bs.mcb.2020.03.011. Epub 2020 May 19. PMID: 32586450
Pluripotent-Stem-Cell-Derived Hepatic Cells: Hepatocytes and Organoids for Liver Therapy and Regeneration.
Messina A, Luce E, Hussein M, Dubart-Kupperschmitt A.
Cells. 2020 Feb 12;9(2):420.
doi: 10.3390/cells9020420. PMID: 32059501
The endothelium, a key actor in organ development and hPSC-derived organoid vascularization.
Vargas-Valderrama A, Messina A, Mitjavila-Garcia MT, Guenou H.
J Biomed Sci. 2020 May 22;27(1):67.
doi: 10.1186/s12929-020-00661-y. PMID: 32443983

Hépatinov develops innovative therapeutic
and diagnostic approaches for hepatic pathologies