Mechanisms of liver regeneration and disease across scales; from molecules to cells and tissue

Despite recent advances, the principles that regulate liver regeneration and how their deregulation leads to disease remain largely unknown. The main goal of this application is to uncover molecular and cellular principles that govern liver regeneration and disease and exploit this knowledge to develop more complex multicellular organoid systems capable of reconstructing liver tissue in a dish. We will adopt a multi-scale (from molecule to tissue), and multidisciplinary approach, addressing the interplay between cell-intrinsic and cell-extrinsic mechanisms in damage paradigms that result in repair vs disease.In Aim 1 we will identify the genomic loci (e.g. Transcription factors, signalling pathways or epigenetic regulators) involved in regeneration and disease, to gain a systems-level understanding of the gene regulatory mechanisms driving liver regeneration and disease. In Aim 2 we will investigate the biochemical signals mediated through cell-cell interactions between ductal cells and mesenchymal, to gain mechanistic understanding on how epithelial – mesenchymal cellular interactions regulate regeneration and their role in disease, particularly fibrosis.In Aim 3 we will build complex multicellular organoids to reconstruct the liver lobule cellular interactions and architecture.An in-depth understanding of the molecular and cellular mechanisms driving tissue regeneration and their deregulation in disease holds the potential to uncover new principles of liver biology. The generation of complex multicellular organoids that recapitulate liver cellular interactions and architecture will provide valuable tools for future mechanistic studies aiming at investigating molecular and cellular principles of tissue maintenance, repair and disease. Transferring these to human tissues will facilitate future studies addressing the long-standing question as to which principles of repair are conserved in humans and which are human specific.