Insights from a Danish study shed light on potential treatment routes for metabolic dysfunction-associated steatohepatitis (MASH).

Previously unknown changes in the liver’s stellate cells show potential for treating chronic liver disease in the future.

This was the main finding in a study led by Associate Professor Kim Ravnskjær from the Department of Biochemistry and Molecular Biology (BMB) and the ATLAS Center of Excellence at the University of Southern Denmark (SDU). The results were published in the article ‘Single cell-resolved study of advanced murine MASH reveals a homeostatic pericyte signaling module’ in Journal of Hepatology.

We had a chat with three of the authors, Daniel Hansen, Peter R. Jakobsgaard, and Trine Vestergaard Dam, to hear more about the study. Daniel Hansen and Trine Vestergaard Dam have received PhD scholarships from Danish Diabetes Academy.

Uncovering the Unknown

Metabolic dysfunction-associated steatohepatitis (MASH, formerly called NASH) is characterised by hepatic inflammation, microvascular dysfunction, steatosis, and fibrotic scarring. With development of metabolic liver disease, activated hepatic stellate cells are responsible for fibrosis formation, often driven by physical inactivity, obesity, and type-2 diabetes.

“We were interested in understanding hepatic stellate cells because they are instrumental in developing liver diseases. Still today, we know so little about these pericyte-like cells as contributors of liver disease,” says Daniel Hansen, one of the chief authors of the article.

Paving the Way for Future Treatment

The SDU team found previously unknown changes in the hepatic stellate cells that have the potential to halt the process of fibrosis formation.

“What we discovered was a change in cellular signalling between not just the stellate cells, but also other cell types in the liver. With activated hepatic stellate cells driving fibrogenesis, these findings could lead to figuring out a potential treatment,” explains Daniel Hansen.

There is currently no FDA-approved treatment for MASH, making these findings all the more significant for future studies and potential drug development.

From Mice to Men

The SDU team studied the cellular changes in mice with advanced MASH, which was obtained by consumption of a Western-style diet. The cellular changes found in the mice were then contextualised to humans by studying tissue from human livers. The human samples were acquired through a collaboration with clinicians at Esbjerg Hospital (partners in the ATLAS Center of Excellence).

“The samples were obtained as biopsies done in connection with gastric bypass operations. With patients consenting and fitting our criteria, we were able to get tissue for analysis. This was a very unique opportunity,” Daniel Hansen explains.

“We were able to do histological analyses of the human tissue that coincided with the main results from the mouse study, but we will need to do further screenings to find new protein targets for possible treatment in human liver disease,” says Daniel Hansen.

When Collaboration Thrives

Sometimes, the right people come together at the right time to achieve something big. This study seems to have been one of those rare occasions, as the list of authors boasts a wide variety of expertise.

“I cannot think of another research project from our hands that has been quite as collaboration-centered as this one. Everyone contributed with their own niche piece to the puzzle,” says Daniel Hansen.

As Daniel Hansen explains it, he took part in the ‘hands-on’ work in the lab, working with the different mouse and human liver samples. Peter R. Jakobsgaard, another chief author of the article, contributed to the study with his expertise in computational biomedicine.

“I spend most of my research behind a computer screen rather than in the lab, working with computational analyses and statistics. I was responsible for the majority of the single-cell analysis in this study,” Peter R. Jakobsgaard explains.

Another one of the authors, Trine Vestergaard Dam, contributed to the study with her specialisation in identifying the gene-regulatory networks driving MASH.

“In my PhD project, we investigated how the DNA structure changes in MASH, focusing on the regulatory aspects of gene expression. And that was what we supplied to this study – chromatin data from our research to give additional insight to what controls the hepatic stellate cell identity,” Trine Vestergaard Dam says.

With the single-cell sequencing done in-house at SDU, and with the researchers often being no more than a few meters apart, the practical conditions for the study were also extremely favourable, as the three researchers explain.

“While writing the paper, we all became more and more proud of what we had achieved as a team. We discussed it afterward – if we could do another study like this, benefiting from so many diverse skills, we would do it in a heartbeat,” concludes Daniel Hansen.

About the Authors

Daniel Hansen is a postdoc at the Functional Genomics and Metabolism Research unit (FGM) found at the Department of Biochemistry and Molecular Biology (BMB) at the University of Southern Denmark. He is a former Danish Diabetes Academy (DDA, now DDEA) grant recipient.

Peter R. Jakobsgaard is a PhD fellow at the FGM, BMB at the University of Southern Denmark.

Trine Vestergaard Dam is a postdoc at FGM, BMB at the University of Southern Denmark. She is a former DDA grant recipient.

Article

Single cell-resolved study of advanced murine MASH reveals a homeostatic pericyte signaling module

Sofie M. Bendixen*, Peter R. Jakobsgaard*, Daniel Hansen*, Kamilla H. Hejn*, Mike K. Terkelsen, Frederik A. Bjerre, Annemette P. Thuelsen, Niels G. Eriksen, Philip Hallenborg, Yana Geng, Trine V. Dam, Frederik T. Larsen, Charlotte W. Wernberg, Janusa Vijayathurai, Emma A.H. Scott, Ann-Britt Marcher, Sönke Detlefsen, Lars Grøntved, Henrik Dimke, Rebecca Berdeaux, Thomas Q. de Aguiar Vallim, Peter Olinga, Mette M. Lauridsen, Aleksander Krag, Blagoy Blagoev, Kim Ravnskjær.

*Contributed equally.

Journal of Hepatology (November 2023) DOI: https://doi.org/10.1016/j.jhep.2023.11.001