Hepatic stellate cell single cell atlas reveals a highly similar activation process across liver disease aetiologies

Vincent Merens; Elisabeth Knetemann; Elif Gürbüz; Vincent De Smet; Nouredin Messaoudi; Hendrik Reynaert; Stefaan Verhulst; Leo A. van Grunsven

doi:10.1016/j.jhepr.2024.101223

Hepatic stellate cell single cell atlas reveals a highly similar activation process across liver disease aetiologies

Vincent Merens, Elisabeth Knetemann, Elif Gürbüz, Vincent De Smet, Nouredin Messaoudi, Hendrik Reynaert, Stefaan Verhulst, Leo A. van Grunsven

Onderzoeksoutput: Article › peer review

1 Citaat (Scopus)

1 Downloads (Pure)

Samenvatting

Background & Aims: The progression of chronic liver disease (CLD) is characterized by excessive extracellular matrix deposition,
disrupting hepatic architecture and function. Upon liver injury, hepatic stellate cells (HSCs) differentiate towards myofibroblasts
and become inflammatory, proliferative and fibrogenic. To date, it is still unclear whether HSC activation is driven by similar
mechanisms in different aetiologies.
Methods: HSCs from multiple publicly available single-cell RNA-sequencing datasets were annotated and merged into a singlecell HSC activation atlas. Spheroid co-cultures of primary mouse hepatocytes/HSCs (n = 5) and ELISAs on patient plasma
samples (n = 80) were performed to validate the mechanistic insight obtained from the HSC atlas.
Results: We established an HSC activation atlas in which HSCs are clearly divided into three distinct transcriptomic profiles:
quiescent HSCs, initiatory HSCs and myofibroblasts. These transcriptomic profiles are present in each of the investigated mouse
liver injury models as well as in human CLDs, indicating that HSC activation is a conserved process. This activation process is
driven by a core set of transcription factors independent of liver injury or species. Furthermore, we reveal novel ligands associated
with activation of HSCs in multiple liver injury models and validate the profibrotic effect of parathyroid hormone. Finally, we identify
COLEC10 as a conserved marker for quiescent HSCs and a biomarker of liver fibrosis in patients with different CLDs (p <0.0001).
Conclusions: We reveal unexpected similarities in the regulatory mechanisms of HSCs across diverse liver injury settings and
species. The HSC activation atlas has the potential to provide novel insights into liver fibrosis and steer novel treatment options.
© 2024 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/

Originele taal-2	English
Artikelnummer	101223
Pagina's (van-tot)	1-12
Aantal pagina's	12
Tijdschrift	JHEP reports
Volume	7
Nummer van het tijdschrift	1
DOI's	https://doi.org/10.1016/j.jhepr.2024.101223
Status	Published - jan 2025

Bibliografische nota

Publisher Copyright:
© 2024 The Author(s)

Keywords

Chronic liver disease
Single-cell RNA-sequencing
parathyroid hormone
COLEC10

Toegang tot document

10.1016/j.jhepr.2024.101223Licentie: CC BY-NC-ND

PIIS2589555924002271Final published version, 3,12 MBLicentie: CC BY-NC-ND

Andere bestanden en links

Link naar publicatie in Scopus

Citeer dit

@article{647fd05751c14bea85b9f084a53f5898,

title = "Hepatic stellate cell single cell atlas reveals a highly similar activation process across liver disease aetiologies",

abstract = "Background & Aims: The progression of chronic liver disease (CLD) is characterized by excessive extracellular matrix deposition, disrupting hepatic architecture and function. Upon liver injury, hepatic stellate cells (HSCs) differentiate towards myofibroblasts and become inflammatory, proliferative and fibrogenic. To date, it is still unclear whether HSC activation is driven by similar mechanisms in different aetiologies. Methods: HSCs from multiple publicly available single-cell RNA-sequencing datasets were annotated and merged into a single-cell HSC activation atlas. Spheroid co-cultures of primary mouse hepatocytes/HSCs (n = 5) and ELISAs on patient plasma samples (n = 80) were performed to validate the mechanistic insight obtained from the HSC atlas. Results: We established an HSC activation atlas in which HSCs are clearly divided into three distinct transcriptomic profiles: quiescent HSCs, initiatory HSCs and myofibroblasts. These transcriptomic profiles are present in each of the investigated mouse liver injury models as well as in human CLDs, indicating that HSC activation is a conserved process. This activation process is driven by a core set of transcription factors independent of liver injury or species. Furthermore, we reveal novel ligands associated with activation of HSCs in multiple liver injury models and validate the profibrotic effect of parathyroid hormone. Finally, we identify COLEC10 as a conserved marker for quiescent HSCs and a biomarker of liver fibrosis in patients with different CLDs (p <0.0001). Conclusions: We reveal unexpected similarities in the regulatory mechanisms of HSCs across diverse liver injury settings and species. The HSC activation atlas has the potential to provide novel insights into liver fibrosis and steer novel treatment options. Impact and implications: This study establishes a single-cell atlas of hepatic stellate cells across various liver injuries, highlighting a conserved activation process between different injuries and across species. The discovery of novel activating ligands and the biomarker COLEC10 in human plasma could be used to enhance diagnostic and therapeutic strategies. Additionally, the conserved activation process supports the use of any mouse model for mechanistic studies and testing of new anti-fibrotic compounds, streamlining preclinical research efforts.",

keywords = "Chronic liver disease, COLEC10, parathyroid hormone, single-cell RNA-Sequencing, Chronic liver disease, Single-cell RNA-sequencing, parathyroid hormone, COLEC10",

author = "Vincent Merens and Elisabeth Knetemann and Elif G{\"u}rb{\"u}z and {De Smet}, Vincent and Nouredin Messaoudi and Hendrik Reynaert and Stefaan Verhulst and {van Grunsven}, {Leo A.}",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s)",

year = "2025",

month = jan,

doi = "10.1016/j.jhepr.2024.101223",

language = "English",

volume = "7",

pages = "1--12",

journal = "JHEP reports",

issn = "2589-5559",

publisher = "Elsevier",

number = "1",

}

Hepatic stellate cell single cell atlas reveals a highly similar activation process across liver disease aetiologies. / Merens, Vincent ; Knetemann, Elisabeth ; Gürbüz, Elif ; De Smet, Vincent ; Messaoudi, Nouredin ; Reynaert, Hendrik ; Verhulst, Stefaan ; van Grunsven, Leo A.

In: JHEP reports, Vol. 7, Nr. 1, 101223, 01.2025, blz. 1-12.

Onderzoeksoutput: Article › peer review

TY - JOUR

T1 - Hepatic stellate cell single cell atlas reveals a highly similar activation process across liver disease aetiologies

AU - Merens, Vincent

AU - Knetemann, Elisabeth

AU - Gürbüz, Elif

AU - De Smet, Vincent

AU - Messaoudi, Nouredin

AU - Reynaert, Hendrik

AU - Verhulst, Stefaan

AU - van Grunsven, Leo A.

PY - 2025/1

Y1 - 2025/1

N2 - Background & Aims: The progression of chronic liver disease (CLD) is characterized by excessive extracellular matrix deposition, disrupting hepatic architecture and function. Upon liver injury, hepatic stellate cells (HSCs) differentiate towards myofibroblasts and become inflammatory, proliferative and fibrogenic. To date, it is still unclear whether HSC activation is driven by similar mechanisms in different aetiologies. Methods: HSCs from multiple publicly available single-cell RNA-sequencing datasets were annotated and merged into a single-cell HSC activation atlas. Spheroid co-cultures of primary mouse hepatocytes/HSCs (n = 5) and ELISAs on patient plasma samples (n = 80) were performed to validate the mechanistic insight obtained from the HSC atlas. Results: We established an HSC activation atlas in which HSCs are clearly divided into three distinct transcriptomic profiles: quiescent HSCs, initiatory HSCs and myofibroblasts. These transcriptomic profiles are present in each of the investigated mouse liver injury models as well as in human CLDs, indicating that HSC activation is a conserved process. This activation process is driven by a core set of transcription factors independent of liver injury or species. Furthermore, we reveal novel ligands associated with activation of HSCs in multiple liver injury models and validate the profibrotic effect of parathyroid hormone. Finally, we identify COLEC10 as a conserved marker for quiescent HSCs and a biomarker of liver fibrosis in patients with different CLDs (p <0.0001). Conclusions: We reveal unexpected similarities in the regulatory mechanisms of HSCs across diverse liver injury settings and species. The HSC activation atlas has the potential to provide novel insights into liver fibrosis and steer novel treatment options. Impact and implications: This study establishes a single-cell atlas of hepatic stellate cells across various liver injuries, highlighting a conserved activation process between different injuries and across species. The discovery of novel activating ligands and the biomarker COLEC10 in human plasma could be used to enhance diagnostic and therapeutic strategies. Additionally, the conserved activation process supports the use of any mouse model for mechanistic studies and testing of new anti-fibrotic compounds, streamlining preclinical research efforts.

AB - Background & Aims: The progression of chronic liver disease (CLD) is characterized by excessive extracellular matrix deposition, disrupting hepatic architecture and function. Upon liver injury, hepatic stellate cells (HSCs) differentiate towards myofibroblasts and become inflammatory, proliferative and fibrogenic. To date, it is still unclear whether HSC activation is driven by similar mechanisms in different aetiologies. Methods: HSCs from multiple publicly available single-cell RNA-sequencing datasets were annotated and merged into a single-cell HSC activation atlas. Spheroid co-cultures of primary mouse hepatocytes/HSCs (n = 5) and ELISAs on patient plasma samples (n = 80) were performed to validate the mechanistic insight obtained from the HSC atlas. Results: We established an HSC activation atlas in which HSCs are clearly divided into three distinct transcriptomic profiles: quiescent HSCs, initiatory HSCs and myofibroblasts. These transcriptomic profiles are present in each of the investigated mouse liver injury models as well as in human CLDs, indicating that HSC activation is a conserved process. This activation process is driven by a core set of transcription factors independent of liver injury or species. Furthermore, we reveal novel ligands associated with activation of HSCs in multiple liver injury models and validate the profibrotic effect of parathyroid hormone. Finally, we identify COLEC10 as a conserved marker for quiescent HSCs and a biomarker of liver fibrosis in patients with different CLDs (p <0.0001). Conclusions: We reveal unexpected similarities in the regulatory mechanisms of HSCs across diverse liver injury settings and species. The HSC activation atlas has the potential to provide novel insights into liver fibrosis and steer novel treatment options. Impact and implications: This study establishes a single-cell atlas of hepatic stellate cells across various liver injuries, highlighting a conserved activation process between different injuries and across species. The discovery of novel activating ligands and the biomarker COLEC10 in human plasma could be used to enhance diagnostic and therapeutic strategies. Additionally, the conserved activation process supports the use of any mouse model for mechanistic studies and testing of new anti-fibrotic compounds, streamlining preclinical research efforts.

KW - Chronic liver disease

KW - COLEC10

KW - parathyroid hormone

KW - single-cell RNA-Sequencing

KW - Chronic liver disease

KW - Single-cell RNA-sequencing

KW - parathyroid hormone

KW - COLEC10

UR - http://www.scopus.com/inward/record.url?scp=85211632021&partnerID=8YFLogxK

U2 - 10.1016/j.jhepr.2024.101223

DO - 10.1016/j.jhepr.2024.101223

M3 - Article

AN - SCOPUS:85211632021

VL - 7

SP - 1

EP - 12

JO - JHEP reports

JF - JHEP reports

SN - 2589-5559

IS - 1

M1 - 101223

ER -