Multi-modal analysis of human hepatic stellate cells identifies novel therapeutic targets for metabolic dysfunction-associated steatotic liver disease
Herein, we present the results of a multi-modal sequencing analysis of human hepatic stellate cells (HSCs) from NORMAL, MASL (metabolic dysfunction-associated steatotic liver), and metabolic dysfunction-associated steatohepatitis (MASH) livers. We identified additional subclusters that were not detected by previous studies and characterized the mechanism by which HSCs are activated in MASH livers, including the transcriptional machinery that induces the transdifferentiation of HSCs into myofibroblasts. For the first time, we described the pathogenic role of activated HSC-derived PAI-1 (a product of the SERPINE1 gene) in the development of MASH liver fibrosis. Targeting the RUNX1/2-SERPINE1 axis could be a novel strategy for the treatment of liver fibrosis in patients.
Authors
- Justin Buchanan (ORCID: https://orcid.org/0000-0001-5904-222X)
- Huayi Zhao
- Sebastian Preißl (ORCID: https://orcid.org/0000-0001-8971-5616)
- David A. Brenner (ORCID: https://orcid.org/0000-0003-2573-525X)
- Tatiana Kisseleva (ORCID: https://orcid.org/0000-0001-9107-2306)
- Cuijuan Han (ORCID: https://orcid.org/0000-0002-7165-7785)
- Daisy Chilin-Fuentes
- Charlene Miciano
- Allen Wang (ORCID: https://orcid.org/0000-0001-9870-7888)
- Michael Miller (ORCID: https://orcid.org/0000-0003-0781-7868)
- Olivier Poirion (ORCID: https://orcid.org/0000-0002-0429-7003)
- Sara Brin Rosenthal (ORCID: https://orcid.org/0000-0002-9072-8032)
- Xiaomeng Hou (ORCID: https://orcid.org/0000-0002-5453-9015)
- Bing Ren (ORCID: https://orcid.org/0000-0002-5435-1127)
- Karin Diggle
- Sadatsugu Sakane (ORCID: https://orcid.org/0000-0002-6306-4621)
- Hyun Young Kim (ORCID: https://orcid.org/0009-0006-2497-6229)
- Xiao Liu (ORCID: https://orcid.org/0000-0002-1541-5546)
- Raquel Carvalho‐Gontijo Weber
- Wonseok Lee
- Christopher K. Glass
- Mojgan Housseini
Institutions
- University of Freiburg (DE)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Discovery Institute (US)
- UC San Diego Health System (US)
- University of California San Diego (US)
Publication Details
- Journal
- Journal of Hepatology
- Published
- 2024-11-08
- DOI
- https://doi.org/10.1016/j.jhep.2024.10.044
- Citations
- 43
- Primary Topic
- Liver Disease Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 16.62
Funders
- National Research Foundation
- National Research Foundation of Korea
- National Institutes of Health
- University of California, San Diego
- School of Medicine, University of California, San Diego