Hepatic immune environment differences among common mouse strains in models of MASH and liver cancer

Patrick Huang; Francisco J Rodriguez-Matos; Jonathan Qi; Rajiv Trehan; Yuta Myojin; Xiao Bin Zhu; Tim F Greten; Chi Ma

doi:10.1016/j.jhepr.2025.101380

Hepatic immune environment differences among common mouse strains in models of MASH and liver cancer

JHEP Rep. 2025 Mar 1;7(5):101380. doi: 10.1016/j.jhepr.2025.101380. eCollection 2025 May.

Authors

Patrick Huang¹, Francisco J Rodriguez-Matos¹, Jonathan Qi¹, Rajiv Trehan¹, Yuta Myojin¹, Xiao Bin Zhu¹, Tim F Greten^{1

2}, Chi Ma¹

Affiliations

¹ Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
² NCI CCR Liver Cancer Program, National Institutes of Health, Bethesda, MD, USA.

Abstract

Background & aims: Inbred mouse strains are critical tools for studying immune regulation of metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC). Here, we profiled mouse strain-associated hepatic immune differences, and performed mice-human cross-species immune comparisons.

Methods: Immune landscapes of C57BL/6, BALB/c, and FVB/N mice were compared under healthy, MASH, or HCC state using high-dimensional spectral flow cytometry (n = 4 per condition). MASH was induced by feeding methionine- and choline-deficient or Western diet + carbon tetrachloride. HCC was caused by hydrodynamic plasmid injection of MYC/sg-p53. Public mouse and human scRNA-seq datasets were used for validation and cross-species comparisons.

Results: In healthy mice, liver CD4⁺ T (24% vs. 14% vs. 34%, p <0.05) and B cells (36.5% vs. 35% vs.18%, p <0.05) varied the most among three strains. C57BL/6 mice showed T_H1 dominance, whereas BALB/c and FVB/N mice had T_H2 dominance (log[T_H1:T_H2] = 0.17, -0.31, -0.17). In MASH mice, expansion of liver myeloid cells and innate lymphocytes were commonly found, but changes of B cells (log(fold-change) = -0.38, -0.28, -0.58, p <0.05) and T subsets (e.g. CD4⁺ T log(fold-change) = -0.21, -0.07, -0.15, p <0.05) varied greatly among strains. MYC/sg-p53 HCC induced a consistent expansion of liver Tregs and CD8⁺ T cells (p <0.05), but differential shifts of liver immune landscape were seen among strains. The flow cytometry data was supported by public scRNA-seq datasets matching C57BL/6 background. Further cross-species comparison in MASH condition confirmed shared changes of adaptive lymphocytes between mice and humans. In two MASH models, BALB/c or C57BL/6 mice were more consistent to recapture loss of CD4⁺ T or B cells, respectively (p <0.05).

Conclusions: Substantial liver immune differences exist among common mouse strains. Mice can recapitulate certain human liver immune changes with strain variations.

Impact and implications: Our immune cell profiling study revealed that the liver immune environment can be quite different among common mouse strains both under healthy and pathologic states, such as steatohepatitis or neoplastic processes. Our results serve as a data resource for studies investigating liver immunology and provide valuable insights for the design of studies on various immune cells in the livers of mice.

Keywords: Immune regulation; Liver cancer; Metabolic dysfunction-associated steatohepatitis; Mouse strain.