Hormone correction of dysfunctional metabolic gene expression in stem cell-derived liver tissue

Alvile Kasarinaite; Maria Mateos Jimenez; Mariana Sierra Beltran; Elena Sutherland; Pedro Arede Rei; Make Zhao; Ying Chi; Meryam Beniazza; Andrea Corsinotti; Timothy J. Kendall; Neil C Henderson; Jonathan A Fallowfield; Philippa T K  Saunders; David Hay

doi:10.1186/s13287-025-04238-0

Hormone correction of dysfunctional metabolic gene expression in stem cell-derived liver tissue

Alvile Kasarinaite, Maria Mateos Jimenez, Mariana Sierra Beltran, Elena Sutherland, Pedro Arede Rei, Make Zhao, Ying Chi, Meryam Beniazza, Andrea Corsinotti, Timothy J. Kendall, Neil C Henderson, Jonathan A Fallowfield, Philippa T K Saunders, David Hay

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Article number	130
Journal	Stem Cell Research and Therapy
Volume	16
Issue number	1
DOIs	https://doi.org/10.1186/s13287-025-04238-0
Publication status	Published - 11 Mar 2025

Keywords / Materials (for Non-textual outputs)

Differentiation
Estrogen
Fibrosis
Human
In vitro models
Liver
MASH
MASLD
Metabolism
Pluripotent stem cells
Single nuclei RNA sequencing
Testosterone
Tissue engineering
Transcriptomics

Access to Document

10.1186/s13287-025-04238-0

Kasarinaite et al_manuscript 2025 SCRT for PUREAccepted author manuscript, 1.11 MB
s13287-025-04238-0Final published version, 1.52 MB

Modelling Sex Dependent Differences in Human Liver Disease using Stem Cell-Derived Models and Organ on a Chip Devices
Hay, D. (Principal Investigator)
Novo Nordisk A/S
1/10/20 → 30/09/24
Project: Research

Single-cell multi-omics
Corsinotti, A. (Manager), Beniazza, M. (Manager) & Bestard Cuche, N. (Other)
Centre for Regenerative Medicine
Facility/equipment: Facility

Cite this

Kasarinaite, A., Mateos Jimenez, M., Sierra Beltran, M., Sutherland, E., Arede Rei, P., Zhao, M., Chi, Y., Beniazza, M., Corsinotti, A., Kendall, T. J., Henderson, N. C., Fallowfield, J. A., Saunders, P. T. K., & Hay, D. (2025). Hormone correction of dysfunctional metabolic gene expression in stem cell-derived liver tissue. Stem Cell Research and Therapy, 16(1), Article 130. https://doi.org/10.1186/s13287-025-04238-0

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title = "Hormone correction of dysfunctional metabolic gene expression in stem cell-derived liver tissue",

abstract = "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 {\textquoteleft}in the dish{\textquoteright}. 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.",

keywords = "Differentiation, Estrogen, Fibrosis, Human, In vitro models, Liver, MASH, MASLD, Metabolism, Pluripotent stem cells, Single nuclei RNA sequencing, Testosterone, Tissue engineering, Transcriptomics",

author = "Alvile Kasarinaite and {Mateos Jimenez}, Maria and {Sierra Beltran}, Mariana and Elena Sutherland and {Arede Rei}, Pedro and Make Zhao and Ying Chi and Meryam Beniazza and Andrea Corsinotti and Kendall, {Timothy J.} and Henderson, {Neil C} and Fallowfield, {Jonathan A} and Saunders, {Philippa T K} and David Hay",

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month = mar,

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doi = "10.1186/s13287-025-04238-0",

language = "English",

volume = "16",

journal = "Stem Cell Research and Therapy",

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Kasarinaite, A, Mateos Jimenez, M, Sierra Beltran, M, Sutherland, E , Arede Rei, P, Zhao, M, Chi, Y, Beniazza, M, Corsinotti, A, Kendall, TJ , Henderson, NC , Fallowfield, JA , Saunders, PTK & Hay, D 2025, 'Hormone correction of dysfunctional metabolic gene expression in stem cell-derived liver tissue', Stem Cell Research and Therapy, vol. 16, no. 1, 130. https://doi.org/10.1186/s13287-025-04238-0

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T1 - Hormone correction of dysfunctional metabolic gene expression in stem cell-derived liver tissue

AU - Kasarinaite, Alvile

AU - Mateos Jimenez, Maria

AU - Sierra Beltran, Mariana

AU - Sutherland, Elena

AU - Arede Rei, Pedro

AU - Zhao, Make

AU - Chi, Ying

AU - Beniazza, Meryam

AU - Corsinotti, Andrea

AU - Kendall, Timothy J.

AU - Henderson, Neil C

AU - Fallowfield, Jonathan A

AU - Saunders, Philippa T K

AU - Hay, David

PY - 2025/3/11

Y1 - 2025/3/11

N2 - 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.

AB - 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.

KW - Differentiation

KW - Estrogen

KW - Fibrosis

KW - Human

KW - In vitro models

KW - Liver

KW - MASH

KW - MASLD

KW - Metabolism

KW - Pluripotent stem cells

KW - Single nuclei RNA sequencing

KW - Testosterone

KW - Tissue engineering

KW - Transcriptomics

U2 - 10.1186/s13287-025-04238-0

DO - 10.1186/s13287-025-04238-0

M3 - Article

SN - 1757-6512

VL - 16

JO - Stem Cell Research and Therapy

JF - Stem Cell Research and Therapy

IS - 1

M1 - 130

ER -

Hormone correction of dysfunctional metabolic gene expression in stem cell-derived liver tissue

Abstract

Keywords / Materials (for Non-textual outputs)

Access to Document

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Projects

Modelling Sex Dependent Differences in Human Liver Disease using Stem Cell-Derived Models and Organ on a Chip Devices

Equipment

Single-cell multi-omics

Cite this