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.
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.
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.
(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.
