Initiation of hepatic stellate cell activation extends into chronic liver disease

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.

Improved Precision-Cut Liver Slice Cultures for Testing Drug-Induced Liver Fibrosis

“…PCA plot shows a division of CTR and VPA treated slices over PC1, which accounts for 34% of variance ( Figure 2F ). Moreover, the fibrogenic aHSC gene signature recently identified by De Smet et al ( 9 ), is significantly enriched in standard PCLS culture conditions when compared to VPA supplemented conditions ( Figure 2G ). Differential gene expression analysis showed that 48 genes were differentially upregulated and 130 genes were differentially downregulated (such as Aebp1, Col1a1 , and Col3a1) in the presence of VPA compared to control conditions (data not shown).…”

“…Traditionally, in vitro models of liver fibrosis rely on 2D cultures of primary HSCs. However, while these in vitro activated HSCs partly resemble their in vivo counterpart, they do not fully recapitulate in vivo HSC activation ( 7 – 9 ). The possible reason for this discrepancy is the loss of micro-environmental context in these 2D cultures.…”

Poly(2-oxazoline) Homopolymers and Diblock Copolymers Containing Retinoate ω-End Groups

“…The varied molar mass entails altering the copolymer composition as the DP value of the PNonOx segments was kept constant while the DP value of the PEtOx segments changed. This was evident from characterization data obtained by 1 H NMR spectroscopy (Figures 3 and S8). The spectra revealed signals ascribed to the PNonOx (capital letters "A− E") as well as the PEtOx (small letters "a−c") segments, which were partially overlapping with each other.…”

“…It is characterized by cell death, immune cell activation, and the increased production and deposition of collagen from activated hepatic stellate cells (HSCs). The activation and collagen production by stellate cells is a hallmark and driving force for the liver fibrotization that results in liver cirrhosis . Thus, interfering with HSC activation and collagen production represents a promising avenue to treat chronic liver diseases.…”

“…The activation and collagen production by stellate cells is a hallmark and driving force for the liver fibrotization that results in liver cirrhosis. 1 Thus, interfering with HSC activation and collagen production represents a promising avenue to treat chronic liver diseases. HSCs store 50−80% of the body's vitamin A 2 and control the vitamin A homeostasis by needindependent vitamin A uptake and release.…”