Ongoing Projects

Mechanobiology of Chronic Liver Disease:

Liver cirrhosis, the end-stage of advanced chronic liver disease (ACLD), is a leading cause of adult mortality in Europe. ACLD progression involves pro-fibrogenic changes in liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs), leading to increased vascular resistance and extracellular matrix deposition. This project investigates the mechanistic link between extracellular matrix stiffness, intercellular communication, and nuclear tension in liver fibrosis. We employ genetically modified mouse models to dissect cellular crosstalk mediated by the endothelial CCL22-CCR4 axis under conditions of increased mechanical forces. Using conditional knockout and reporter mice, we modulate signaling between endothelial cells, immune cells, and HSCs to identify how mechanical cues—including matrix stiffness and sinusoidal pressure—drive fibrogenic responses. This work examines nuclear mechanoprotective mechanisms remodeling in both 2D and 3D culture systems, complemented by in vivo validation in MASH and fibrosis models. The study aims to uncover novel therapeutic targets by elucidating how liver stiffness perpetuates hepatic fibrosis through mechanotransduction pathways.

Exploring Novel Therapeutic Strategies for Liver Cirrhosis and Portal Hypertension:

Chronic liver disease (CLD) is responsible for over 2 million deaths worldwide annually, yet no approved disease-modifying therapies exist. Carvedilol, a non-selective beta-blocker, reduces portal pressure in cirrhotic patients by decreasing splanchnic blood flow, but its intrahepatic mechanisms remain poorly understood. Our project investigates whether carvedilol improves the hepatic microenvironment by enhancing LSEC function and reducing HSC activation. Using rodent models of cirrhosis and portal hypertension, we assess cellular and molecular endpoints through omics and imaging technologies to characterize carvedilol's effects beyond hemodynamic modulation.

In parallel, we explore nanotechnology-based therapies for liver fibrosis. Silymarin (SMR), an antifibrotic compound with promising effects, suffers from limited bioavailability. In collaboration with Prof. Paola Luciani's group, we combine phospholipids with SMR to enhance hepatic uptake and evaluate the antifibrotic effects of nanodrug formulations—such as polyenylphosphatidylcholine (PPC) combined with SMR—in advanced CLD models. This work aims to develop targeted delivery systems that maximize therapeutic efficacy while minimizing systemic exposure.

Epigenetic Changes in Liver Fibrosis:

Traditional in vitro platforms inadequately recapitulate the complex pathophysiological conditions of liver fibrosis in vivo, limiting therapeutic development. This project investigates chromatin remodeling in liver cells across in vitro and in vivo settings to identify epigenetic mechanisms underlying fibrosis. By profiling histone modifications, DNA methylation, and chromatin accessibility in LSECs, HSCs, and hepatocytes, we aim to uncover upstream regulatory events that influence disease progression. Using advanced 2D and 3D culture systems alongside murine fibrosis models, we characterize how mechanical forces and matrix stiffness alter the epigenetic landscape. This research provides fundamental insights into epigenetic regulation of endothelial dysfunction and fibrogenesis, informing the design of epigenetic therapies for CLD.

Mechanisms of Fibrosis Regression in Cirrhosis:

Liver cirrhosis can lead to severe complications, liver transplantation, and death. Clinical evidence supports reversibility of cirrhosis upon removal of the underlying injury, yet the mechanisms of fibrosis regression remain underexplored. Signaling pathways including Hippo, Hedgehog, Notch, and Wnt have been linked to fibrosis, and modulating their activity may promote regression. However, these pathways have not been systematically tested in regression models, and reliable biomarkers to predict therapeutic response are lacking. This project aims to elucidate the molecular mechanisms underlying fibrosis regression in ACLD and cirrhosis using genetic and pharmacological approaches in rodent models. We employ lineage tracing, single-cell RNA sequencing, and functional assays to identify HSC deactivation pathways and characterize changes in the cellular and extracellular microenvironment during regression. Understanding the role of novel pathways in fibrosis resolution could lead to targeted therapies that accelerate recovery, reducing mortality, transplantation needs, and the medical and economic burden of CLD.