mapping-hepatic-stellate-cell-morphology-mouse-models-liver

Mapping Hepatic Stellate Cell Morphology in Mouse Models of Liver Fibrosis

Tissue-resident fibroblasts are the cellular drivers of fibrosis across tissues. Within the liver, hepatic stellate cells (HSCs), the resident pericytes ...

Icahn School of Medicine at Mount Sinai

Hepatic fibrosis is a key predictor of mortality in liver disease, driven by fibrogenic hepatic stellate cells (HSCs). Targeting these fibrogenic cells may therefore offer a therapeutic approach for hepatic fibrosis. We previously showed that in vivo-generated chimeric antigen receptor (CAR) T cells targeting fibroblast activation protein alpha (FAP) reduced murine cardiac fibrosis. Here, we explored the antifibrotic potential of this in vivo-generated anti-FAP CAR T cell therapy in metabolic dysfunction-associated steatohepatitis (MASH), a highly prevalent disease with no approved antifibrotic therapies. We first established that FAP expression in both human and murine MASH is specific to HSCs. We then used flow cytometry, Sirius Red morphometry, digital pathology analysis, and single nuclear RNA sequencing to assess the impact of anti-FAP CAR T cell therapy on murine MASH. Anti-CD5-targeted lipid nanoparticles carrying anti-FAPCAR messenger RNA transiently generated activated anti-FAP CAR T cells, which substantially reduced fibrosis by depleting profibrogenic HSCs. They also modulated immune cells, endothelial cells, and hepatocytes in a non-cell autonomous manner to mitigate inflammation and restore hepatic homeostasis. These findings highlight the potential of in vivo CAR T therapy to attenuate a highly morbid and pervasive liver disease, not only by directly reducing fibrosis but also through indirect effects on other cell types.

Anti-FAP CAR T cells produced in vivo reduce fibrosis and restore liver homeostasis in metabolic dysfunction-associated steatohepatitis.

Fibrosis contributes to ∼40% of mortality in the industrialized world. Fibrosis in the liver can spontaneously resolve when injury terminates. In this study, we establish a robust mouse model of fibrosis regression in MASH (metabolic dysfunction-associated steatohepatitis), a highly prevalent chronic liver disease worldwide, and perform single-cell and in situ molecular profiling to define the molecular drivers of fibrosis regression. Prediction of cell-cell communication identifies a Wnt9b-Sfrp2 crosstalk that emerges as fibrosis resolves, the perturbation of which attenuates spontaneous fibrosis regression. We further identify a subset of liver endothelial cells termed "Endo4" as the source of Wnt9b. Immunostaining for the Endo4 marker VWF using tissue clearing and 3D imaging reveals VWF+ vasculature juxtaposing activated hepatic stellate cells that penetrate deep into the fibrotic septa and exhibit in situ protease activity, establishing them as de facto scar-associated endothelial cells and a regulatory node in murine MASH fibrosis regression.

Article	Year
Anti-FAP CAR T cells produced in vivo reduce fibrosis and restore liver homeostasis in metabolic dysfunction-associated steatohepatitis. Science translational medicine\| PubMed ID: 41564158	2026
Scar-associated endothelial-stellate cellular crosstalk drives fibrosis resolution in MASH. Cell reports\| PubMed ID: 41581151	2026

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