Multi-organ coupling on a chip for metabolic syndrome monitoring
(MSY-OOC)

Coordinators

Cécile Legallais, (BMBI UMR CNRS 7338/UTC), Eric Leclerc, (IRL CNRS 2820 LIMMS/ U Tokyo), Jean-Charles Duclos-Vallée, (Centre Hépato-Biliaire CHB, Hôpital Paul Brousse, Villejuif) 

Institutions and establishments involved

CNRS UMR 8520 IEMN et INSERM U1193 et U996, UMRS 1138 ; Hôpital Antoine Béclère

Context and challenges

Non-alcoholic fatty liver disease (NAFLD, now called MAFLD) is a growing public health problem, affecting 25% of European adults. 10–30% of cases progress to non-alcoholic steatohepatitis (NASH), which can lead to cirrhosis or hepatocellular carcinoma. MAFLD is closely linked to metabolic syndrome (MSy), a complex multi-organ disease associated with pathologies such as type 2 diabetes, obesity and cardiovascular diseases. In Europe, MSy affects up to 36% of the population.

Understanding the mechanisms of disease progression is essential to improve risk stratification for patients and develop innovative treatments. Animal models are insufficient to reproduce human metabolism. Although liver-on-chips are already used for toxicology studies, these models do not fully reproduce the functional unit of the perfused human liver.

To propose and validate new in vitro models, the consortium, with 20 years of experience in liver engineering and microphysiological systems, draws on the international expertise of the Antoine-Béclère Hospital and the CHB, recognized for the management of serious liver disorders and for their translational research units in hepatology.

Scientific objectives and solutions

The goal is to develop a new generation of organs-on-a-chip capable of reproducing cellular interactions and the mechanical and chemical properties of the extracellular matrix (ECM) of the liver, in healthy and pathological conditions, as well as interactions with other organs involved in metabolic syndrome. This model will allow:

To identify new biomarkers and evaluate innovative therapies using data from patient cohorts.

To study the mechanisms of MAFLD onset: lipid accumulation, dysfunction of hepatic sinusoid endothelial cells (LSECs) and activation of stellate cells leading to fibrosis.

To simulate metabolic syndrome (MSy): creation of a demonstrator reproducing the interaction between different organs involved in MSy (liver, adipose tissue, vascular wall), by integrating the effects of the environment or specific diets.

Research program

Reproducing on-chip the structure and functions of a steatotic liver/MAFLD:

Development of a functional sinusoidal barrier by culturing LSECs on a soft matrix, then more rigid to simulate fibrosis.

Accumulation of toxic lipids in hepatocytes to reproduce lipotoxicity.

Co-culture with stellate cells or hepatic macrophages (Kupffer cells) to induce inflammation.

Validation of the model by comparing in vitro data with serological and histological data from patients with MAFLD.

Coupling the key organs of the metabolic syndrome (liver, adipose tissue, vascular wall):

Adaptation of perfusion flows and culture media to simulate physiological and pathological conditions

Use of the patented CCDIM Box platform, allowing to perfuse and couple several organs on a chip in series or in parallel.

Development of a new microfluidic device for multi-organ coupling

Identify biomarkers of MSy progression and evaluate treatments:

Exploitation of data from the LITONAS, ObPlus and PLICATURE cohorts (> 400 patients) with serum, liver and adipose tissue samples.

Validation of biomarkers such as miRNA-122/CK18 levels, pro-inflammatory cytokines, and expression of fibrotic proteins (α-SMA/Col1A1).

Integration of multi-omics data and imaging analyses into in silico models to identify new biomarkers and signaling mechanisms.