LiverSoC

We are developing a new model to study liver health and disease linked to the liver microcapillary, "the sinusoid". Our model aims at restoring with the highest fidelity possible the physicochemical features of this particular microenvironment, to study the role of mechanics and associated molecular pathways involved in all the pathophysiology of the liver (liver transplant, portal hypertension, fibrosis, cirrhosis and hepatocellular carcinoma) and to test new treatments. 

Our approach is to use a microphysiological system (MPS) that mimics the liver sinusoid. with multiple cell types and microfluidics, but with a twist: we are engineering the initial cues to guide the endothelial cells lining the capillary wall to construct their own morphofunctional architecture. The liver sinusoid is indeed a complex structure that consists of liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), hepatocytes and other cell types like immune cells. This vessel plays a key role in liver functions and is involved in the development of multiple diseases, but we have not still identify the precise mechanisms, to expect future treatments of the pathologies. Understanding the response of the LSECs to flow will also be essential in the preparation of liver for transplant, 

Our Liver Sinusoid-on-a-Chip MPS (LiverSoC) is a work in progress to build a device that is recreating the liver sinusoid in a microfluidic chip, first with LSECs and HSCs, then with hepatocytes (a cell type we have worked on in the past with our collaorators in Mexico). Specific media or blood can flow through the channels under specific conditions, which allows us to study the effects of different conditions on the liver sinusoid cells and evaluate molecular responses. This model should recapitulate in vitro the mechanotransduction pathways triggered by hemodynamic forces and inflammation, at both single cell and tissue levels. We will be able to replicate key aspects of some disease (biochemical, hemodynamic) and model the local multicellular changes caused by them. We will also be able to test our model with drugs known to improve hepatic sinusoid conditions in patients and will monitor the system's response at cellular and molecular levels. We aim to validate LiverSoC as a model for future mechanistic studies in which other liver cell types can be incorporated.

In this project, PhD student Ana Ximena Monroy-Romero has identified the adequate conditions for LSECs to form a non-embedded 5-10 µm microvessel with a lumen (please see our recent preprint) and Dr. Wenjin Xiao is currently working on its precise perfusion and co-culture with other cell types towards a true liver sinusoid on a chip. In parallel, PhD student Brenda Nieto-Rivera is now working with iPSCs-derived endothelial cells, to study the synergetical role of mechanical, topographical and molecular cues on LSEC differentiation and homeostasis in liver vessels development.

Project funded partly by Fondation de l'Avenir and i-Bio initiative.