A human liver model leads to therapeutic discovery for liver disease

In this blog, we will discuss how single-cell RNA sequencing contributed to the discovery of a therapeutic for the treatment of advanced liver disease.  

Liver fibrosis can lead to cirrhosis, which is a late-stage liver disease in which a large part of the liver tissue is replaced by fibrotic tissue, and to hepatocellular carcinoma (HCC). Advanced liver disease is a major risk factor for HCC. As the prevalence of advanced liver disease is high, there is a need for drugs that prevent liver disease progression towards cancer development. However, such chemopreventive drugs are still lacking.  

Identification of these drugs for advanced liver disease progression is hampered by the lack of a good model system.  

In this study, the development of a new human cell culture system and the use of various techniques, including single-cell RNA sequencing, contributed to the discovery of a drug for advanced liver disease and HCC chemoprevention. This paper was published in Nature Communications in September 2021.  

Nizatidine to treat advanced liver disease 

In this study, a human liver cell culture system was developed that recapitulates advanced liver disease, based on the expression of a specific gene set, called a prognostic liver signature (PLS). In patient, PLS predicts a poor prognosis of advanced liver disease.  

This liver cell-based system was used to screen for drugs that reverse the PLS poor-prognosis status to a good-prognosis status. One of the compounds found is nizatidine. This drug blocks the histamine receptor H2 (HRH2), which is expressed by hepatocytes and specific macrophages present in the liver.  

By blocking HRH2 with nizatidine, PLS is reverted in the human cell culture model. Furthermore, it reduces liver fibrosis and cancer development in two animal models. This confirms the therapeutic effect of nizatidine in these systems.  

Liver macrophages respond to nizatidine 

To verify the results of the cell culture model, SORT-seq was used in this study to uncover the effect of nizatidine on patient liver immune cells. For this, liver immune cells from patients with advanced liver disease or HCC were isolated and treated with nizatidine or vehicle control. The single-cell RNA technique SORT-seq was used on these cells and performed at Single Cell Discoveries.  

Cells were clustered based on the transcriptomic data, showing that liver macrophages are the main immune cells to respond to nizatidine. So, the therapeutic effect of nizatidine was mediated by the effect on liver macrophages, besides hepatocytes.  Macrophages in the liver can play an important role in liver fibrosis and possibly also tumor progression. It is likely that nizatidine blocks pathways in macrophages to inhibit liver fibrosis progression and tumor progression.  

This study shows that nizatidine could be an interesting treatment option for patients with advanced liver disease to prevent HCC development. Future studies should focus on the translatability of these data to the clinic, hopefully resulting in a safe and efficient treatment of advanced liver disease.  

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