Hormone correction of dysfunctional metabolic gene expression in stem cell-derived liver tissue
The increase in metabolic dysfunction-associated steatotic liver disease (MASLD) and its progression to metabolic dysfunction-associated steatohepatitis (MASH) is a worldwide healthcare challenge. Heterogeneity between men and women in the prevalence and mechanisms of MASLD and MASH is related to differential sex hormone signalling within the liver, and declining hormone levels during aging. In this study we used biochemically characterised pluripotent stem cell derived 3D liver spheres to model the protective effects of testosterone and estrogen signalling on metabolic liver disease 'in the dish'. We identified sex steroid-dependent changes in gene expression which were protective against metabolic dysfunction, fibrosis, and advanced cirrhosis patterns of gene expression, providing new insight into the pathogenesis of MASLD and MASH, and highlighting new druggable targets. Additionally, we highlight gene targets for which drugs already exist for future translational studies.
Authors
- David C. Hay (ORCID: https://orcid.org/0000-0002-7593-5973)
- Philippa T. K. Saunders (ORCID: https://orcid.org/0000-0001-9051-9380)
- Alvile Kasarinaite (ORCID: https://orcid.org/0000-0003-3557-6416)
- Andrea Corsinotti (ORCID: https://orcid.org/0000-0003-4481-0999)
- Elena F. Sutherland (ORCID: https://orcid.org/0000-0003-4636-6350)
- Meryam Beniazza
- Timothy James Kendall (ORCID: https://orcid.org/0000-0002-4174-2786)
- Maria Jiménez Ramos (ORCID: https://orcid.org/0009-0000-8273-0805)
- Jonathan Andrew Fallowfield (ORCID: https://orcid.org/0000-0002-5741-1471)
- Neil Cowan Henderson (ORCID: https://orcid.org/0000-0002-2273-4094)
- Ying Chi (ORCID: https://orcid.org/0000-0002-3020-7892)
- Mariana Beltran-Sierra
- Pedro Arede Rei
- Ming Zhao (ORCID: https://orcid.org/0000-0003-2000-2241)
Institutions
- MRC Centre for Regenerative Medicine (GB)
- MRC Centre for Reproductive Health (GB)
- Centre for Inflammation Research (GB)
- Zhejiang University-University of Edinburgh Institute (CN)
- Institute of Genetics and Cancer (GB)
- University of Edinburgh (GB)
Publication Details
- Journal
- Stem Cell Research & Therapy
- Published
- 2025-03-11
- DOI
- https://doi.org/10.1186/s13287-025-04238-0
- Citations
- 4
- Primary Topic
- Liver Disease Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 5.42
Funders
- Wellcome Trust
- Medical Research Council
- Innovate UK