Initiation of hepatic stellate cell activation extends into chronic liver disease

Vincent De Smet,Georg Halder,Mina Kazemzadeh Dastjerd,Vincent Merens,Inge Mannaerts,Leo A Van Grunsven,Nathalie Eysackers,Stefaan Verhulst

doi:10.1038/s41419-021-04377-1

Abstract

Activated hepatic stellate cells (aHSC) are the main source of extra cellular matrix in liver fibrosis. Activation is classically divided in two phases: initiation and perpetuation. Currently, HSC-based therapeutic candidates largely focus on targeting the aHSCs in the perpetuation phase. However, the importance of HSC initiation during chronic liver disease (CLD) remains unclear. Here, we identified transcriptional programs of initiating and activated HSCs by RNA sequencing, using in vitro and in vivo mouse models of fibrosis. Importantly, we show that both programs are active in HSCs during murine and human CLD. In human cirrhotic livers, scar associated mesenchymal cells employ both transcriptional programs at the single cell level. Our results indicate that the transcriptional programs that drive the initiation of HSCs are still active in humans suffering from CLD. We conclude that molecules involved in the initiation of HSC activation, or in the maintenance of aHSCs can be considered equally important in the search for druggable targets of chronic liver disease.

Highlights

Chronic liver disease (CLD) relates to a spectrum of pathological states of the liver marked by inflammation, fibrosis and disturbed hepatocyte regeneration
Defining the transcriptional programs in hepatic stellate cells (HSCs) during experimental liver fibrosis To achieve our goal of mapping transcriptional dynamics during different stages of HSC activation, we first set out to characterize the transcriptional program in fully activated HSCs seen during peak fibrosis
As liver fibrosis in itself is a process of extracellular matrix (ECM) remodeling, we aimed to define this program by selecting genes that are exclusively intertwined with ECM deposition

Summary

Introduction

Chronic liver disease (CLD) relates to a spectrum of pathological states of the liver marked by inflammation, fibrosis and disturbed hepatocyte regeneration. When present over a prolonged period of time this can lead to the development of cirrhosis, liver failure and hepatocellular carcinoma (HCC). Causes of CLD include nonalcoholic fatty liver disease (NAFLD), viral hepatitis and alcohol abuse. To this day, CLD remains a global health issue accounting for an approximate 150.000 deaths each year in Europe associated with a significant economic burden [1,2,3]. Since the progression of fibrosis to cirrhosis in CLD is associated with an increased morbidity and mortality, developing antifibrotic therapies is an important yet unmet strategy for tackling CLD

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