Regenerative Hepatology

Research focus

The liver sustains reserves of iron, vitamins and minerals and detoxifies alcohol, drugs and other chemicals. The liver has also a function in synthesis by producing albumin which represents the most abundant protein in the plasma, and blood clotting factors. Finally, the liver has an essential metabolic function by storing glycogen and lipids.

Diseases targeting these functions are life threatening, with chronic liver disorders resulting in life-long treatment, a significant reduction in the quality of life, and progression to hepatocellular carcinoma, a form of cancer with very prognosis. Although the therapeutic arsenal has increased in the past decades, treatments for acute liver failure and end-stage chronic liver disease remain limited.

The overarching objective of our research is to understand the basic mechanisms controlling human development and liver biology to develop new therapies against liver diseases. For that we combine in vitro platforms based human Induced pluripotent stem cells (hIPSCs) and organoids with patient’s data and animal models.

hIPSCs and organoids can be derived from almost any patients and then grown indefinitely in large quantity allowing investigations impossible otherwise. Of particular interest, we perform gain and loss of functions experiments using CRISPR/Cas9 genome editing followed by phenotyping analyses taking advantage of state-of-the-art technologies for single cell transcriptomics and epigenomics. We then validate data generated in vitro using patients’ samples and animal model for disease.

This approach allows us to study detailed molecular mechanisms and then validate the interest of these result for clinical applications including drug discovery and regenerative medicine.

Research projects

Liver organogenesis.

The sequential events of differentiation that ensure the emergence of the liver during development have been extensively studied in animal models. The resulting knowledge has been exploited to develop protocols for differentiating human induced Pluripotent Stem Cells (hiPSCs) into a diversity of hepatic cell types. However, this knowledge-based approach has been more challenging to apply to produce fully functional cells, especially hepatocytes. This limitation is due in part to a lack of understanding the mechanisms driving organ maturation in human. Our goal is to address this knowledge gap by understanding the mechanisms directing liver organogenesis. For that, we combine hiPSCs, primary hepatoblast organoids (Figure 1), gain and loss of function approaches and single cell analyses to study human liver development in vitro. Of particular interest, we aim to uncover (i) the molecular mechanisms controlling the specification of hepatocytes and cholangiocytes and (ii) the factors driving the functional maturation of the same cell types.

Endogenous regeneration

The remarkable ability of the liver to regenerate after acute injury is well established and this property is believed to be driven mainly through hepatocyte proliferation. However, regeneration during chronic injury, especially in human, appear to be more complex. Indeed, studies in animal models have shown that 3 mechanisms could take place: (i) activation of liver stem cells, (ii) dedifferentiation/redifferentiation of adult livers cells and (iii) cellular plasticity between cholangiocytes and hepatocytes. However, the evidence confirming the existence of such mechanisms during progression of human chronic liver disease remain to be uncovered. Our goal is to model the regenerative process occurring during  progression non-alcoholic fatty liver disease (NALFD) towards liver failure using hIPSCs derived hepatocytes and cholangiocyes organoids. We are particularly interested in understanding the molecular mechanisms controlling cellular plasticity and how these mechanisms related to developmental program.   

Liver disease

The most rapidly rising cause of liver cirrhosis is non-alcoholic fatty liver disease (NAFLD), which is predicted to shortly become the commonest indication for liver transplantation. NAFLD is linked to obesity and its sequelae, including type 2 diabetes mellitus, though the process of insulin resistance. Consequently, the evolving epidemic of obesity is resulting in a rapidly increasing prevalence of NAFLD with 20-40% of the population suspected to be affected. The pathophysiology of NASH is characterised by toxic lipid accumulation in hepatocytes, the main functional cell type of the liver. The accumulating lipid species result in a number of responses, including oxidative stress, mitochondrial dysfunction and endoplasmic reticulum stress leading to cell death, a pro-inflammatory response, fibrosis and ultimately cirrhosis. The development of new therapies addressing lipotoxicity is currently impaired by the absence of physiologically relevant in vitro models to study NASH and to identify potential drug targets. As a consequence, there have been no long-term effective treatments for this condition. Our aim is to take advantage of hIPSCs and organoid to model NAFLD/NASH in vitro to validate target in the context of drug development.

Cell based therapy.

Cell therapy using Hepatocytes have been proposed as an alternative for organ transplantation which remains the front-line treatment for end stage liver diseases. However, this approach is limited since adult primary hepatocytes are challenging to grow in vitro. For this reason, we have developed protocols to produce hepatocytes and other hepatic cells from human induced pluripotent stem cells (hiPSCs) . hiPSCs are easily derived by direct reprogramming of skin or blood cells from almost any donors. These cells can be grown indefinitely in vitro while maintaining their capacity to differentiate into any cell type. Thus, hiPSCs represent a unique source for the production of cells for cell-based therapy. Accordingly, we take advantage of hiPSCs to develop a self-organizing bioengineered liver containing key hepatic cell types and mimicking the complex architecture of the native organ. These artificial organs will provide long term support to the host liver in the context of chronic disorders.

TEAM | Berlin BIH

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