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Recently, the editorial of Journal of Hepatology discussed the challenges and opportunities in developing anti-fibrotic therapies for liver disease. Despite promising preclinical and early clinical data, many anti-fibrotic drugs have failed in late-stage trials, highlighting the complexity of liver fibrosis and the need for innovative approaches.

The editorial emphasized the importance of targeting non-parenchymal cells (NPCs), particularly liver sinusoidal endothelial cells (LSECs), in the treatment of liver fibrosis. LSECs undergo a process called capillarization during liver disease, characterized by the loss of fenestrations and the formation of a basement membrane. This change disrupts the normal liver sinusoidal architecture and contributes to fibrosis progression.

The editorial highlighted a study by He et al, which identified POFUT1 as a key regulator of LSEC capillarization and fibrosis. POFUT1 controls Notch and STAT3 signaling in LSECs, which in turn influence HSC activation and fibrogenesis. By suppressing POFUT1, the study demonstrated reduced liver fibrosis in mouse models.

The authors suggested that targeting Notch signaling, either through c-secretase inhibitors or antibodies targeting Notch ligands, could be a promising therapeutic strategy. Additionally, investigating the role of STAT3 in LSECs and exploring STAT3 inhibitors could provide further avenues for anti-fibrotic treatment.

The editorial concluded by emphasizing the need for continued research and development of novel anti-fibrotic therapies targeting non-parenchymal cells. These therapies could potentially be used across various liver diseases, offering a valuable addition to the current treatment landscape and improving outcomes for patients with liver fibrosis.

Furthermore, another study conducted by Kaffe et al. represents a significant advancement in our understanding of human liver metabolism and the complex interactions between hepatocytes and their microenvironment. The authors successfully developed a comprehensive and functional human hepatic tissue in a mouse host, enabling the investigation of human-specific metabolic processes and the role of NPCs in regulating hepatocyte function.

The authors employed a two-pronged approach to humanize the liver tissue in mice. First, they utilized the MISTRG6 mouse model, which allows for the robust development of human immune cells upon transplantation of human CD34+ fetal liver cells (FLCs). To expand the humanization scope, they introduced human hepatocytes and human CD34+ FLCs into the MISTRG6 mice, resulting in the establishment of humanized livers containing a majority of human hepatic cell types, including hepatocytes, immune cells, endothelial cells, stellate cells, cholangiocytes, and portal fibroblasts.

The humanized livers exhibited a remarkable resemblance to the cellular composition and tissue architecture of the human liver. The spatial organization of hepatocytes and LSECs within the liver lobule mirrored the zonation pattern observed in humans, with distinct gene expression profiles corresponding to each zone. Moreover, the humanized livers recapitulated key human-specific metabolic functions, such as lipoprotein synthesis and secretion, bile acid metabolism, and the development of non-alcoholic fatty liver disease (NAFLD) upon exposure to a Western diet. These findings demonstrated the functional capacity of the humanized liver and its potential for modeling human liver diseases.

To investigate the regulation of hepatocyte metabolism, the authors compared the transcriptomic and lipidomic profiles of human hepatocytes in the presence and absence of human NPCs. They discovered that the presence of human NPCs significantly altered the expression of genes involved in lipid metabolism, cholesterol metabolism, and transport. Additionally, the lipidomic profile of hepatocytes with human NPCs closely resembled that of human liver tissue, while hepatocytes without human NPCs exhibited deviations from the human-like profile. These results indicated that human NPCs exerted a paracrine influence on hepatocyte metabolism.

Further investigation revealed that the endothelial cell-derived WNT2 ligand played a crucial role in regulating hepatocyte metabolism. Human hepatocytes expressed the FZD5 receptor, which specifically bound to WNT2. Co-culture experiments demonstrated that WNT2 secreted by LSECs enhanced cholesterol uptake and glycine conjugation of bile acids in human hepatocytes. Moreover, silencing WNT2 in LSECs or FZD5 in hepatocytes abolished these effects, confirming the WNT2/FZD5 signaling pathway as a key regulator of human hepatocyte metabolism.

To validate the role of WNT2 and FZD5 in vivo, the authors employed the MISTRG6-RAF model, where endothelial cells were of murine origin. Injection of liposomes containing human WNT2 into these mice resulted in increased cholesterol uptake and glycine conjugation of bile acids in hepatocytes, similar to the effects observed in vitro. Conversely, ablation of FZD5 in hepatocytes using siRNA led to reduced cholesterol uptake and altered bile acid conjugation, further confirming the essential role of the WNT2/FZD5 pathway in regulating hepatocyte metabolism in vivo.

This study highlights the crucial role of NPCs, particularly endothelial cells, in regulating human hepatocyte metabolism. The identification of the WNT2/FZD5 signaling pathway provides a novel target for therapeutic interventions in liver diseases associated with dysregulated lipid metabolism, such as NAFLD and fibrosis. The comprehensive humanized liver model developed in this study offers a valuable tool for investigating the mechanisms underlying human liver biology and pathology, as well as for evaluating potential therapeutic targets. Future research could explore the impact of other NPC-derived factors on hepatocyte metabolism and investigate the potential of modulating the WNT2/FZD5 pathway for treating liver diseases.

References:

1. McGettigan BM, Shah VH. Every sheriff needs a deputy: Targeting non-parenchymal cells to treat hepatic fibrosis. J Hepatol. 2024 Jul;81(1):20-22.

2. Kaffe E, Roulis M, Zhao J, Qu R, Sefik E, Mirza H, Zhou J, Zheng Y, Charkoftaki G, Vasiliou V, Vatner DF, Mehal WZ; AlcHepNet; Yuval Kluger, Flavell RA. Humanized mouse liver reveals endothelial control of essential hepatic metabolic functions. Cell. 2023 Aug 31;186(18):3793-3809.e26.