Author
Listed:
- Raquel A. Martínez García de la Torre
(Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
University of Barcelona)
- Julia Vallverdú
(Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS))
- Zhenqing Xu
(Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
University of Barcelona)
- Silvia Ariño
(Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
University of Barcelona
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd))
- Raquel Ferrer-Lorente
(Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS))
- Laura Zanatto
(Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
University of Barcelona)
- Maria Mercado-Gómez
(Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS))
- Beatriz Aguilar-Bravo
(Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS))
- Paloma Ruiz-Blázquez
(Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
University of Barcelona
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)
Spanish National Research Council (IIBB-CSIC))
- Maria Fernandez- Fernandez
(Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
University of Barcelona
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)
Spanish National Research Council (IIBB-CSIC))
- Artur Navarro-Gascon
(Universitat de Barcelona
Instituto de Salud Carlos III)
- Albert Blasco-Roset
(Universitat de Barcelona
Instituto de Salud Carlos III)
- Paula Sànchez-Fernàndez-de-Landa
(Universitat de Barcelona
The Barcelona Institute of Science and Technology)
- Joan Pera
(Institut d’Investigació Biomèdica de Bellvitge (IDIBELL))
- Damia Romero-Moya
(Institut d’Investigació Biomèdica de Bellvitge (IDIBELL))
- Paula Ayuso Garcia
(University of Santiago de Compostela)
- Celia Martínez Sánchez
(Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
University of Barcelona
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd))
- Laura Sererols Viñas
(Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
University of Barcelona)
- Paula Cantallops Vilà
(Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
University of Barcelona)
- Carmen I. Cárcamo Giráldez
(Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS))
- Andrew McQuillin
(University College London)
- Marsha Y. Morgan
(University College London)
- Daniel Moya-Rull
(Barcelona Institute of Science and Technology (BIST))
- Núria Montserrat
(Barcelona Institute of Science and Technology (BIST)
Catalan Institute for Research and Advanced Studies (ICREA))
- Delphine Eberlé
(U1011-EGID)
- Bart Staels
(U1011-EGID)
- Bénédicte Antoine
(CRSA)
- Mikel Azkargorta
(Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)
Bizkaia Science and Technology Park)
- Juan-José Lozano
(Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd))
- Maria L. Martínez-Chantar
(Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)
Basque Research and Technology Alliance (BRTA))
- Alessandra Giorgetti
(Institut d’Investigació Biomèdica de Bellvitge (IDIBELL)
Barcelona University)
- Félix Elortza
(Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)
Bizkaia Science and Technology Park)
- Anna Planavila
(Universitat de Barcelona
Instituto de Salud Carlos III)
- Marta Varela-Rey
(University of Santiago de Compostela
Barcelona University)
- Ashwin Woodhoo
(University of Santiago de Compostela
Plaza do Obradoiro s/n
Santiago de Compostela)
- Antonio Zorzano
(Universitat de Barcelona
Instituto de Salud Carlos III
The Barcelona Institute of Science and Technology
Instituto de Salud Carlos III)
- Isabel Graupera
(Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)
University of Barcelona)
- Anna Moles
(Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)
Spanish National Research Council (IIBB-CSIC))
- Mar Coll
(Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
University of Barcelona
University of Barcelona)
- Silvia Affo
(Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS))
- Pau Sancho-Bru
(Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)
University of Barcelona)
Abstract
Defining the trajectory of cells during differentiation and disease is key for uncovering the mechanisms driving cell fate and identity. However, trajectories of human cells remain largely unexplored due to the challenges of studying them with human samples. In this study, we investigate the proteome trajectory of iPSCs differentiation to hepatic stellate cells (diHSCs) and identify RORA as a key transcription factor governing the metabolic reprogramming of HSCs necessary for diHSCs’ commitment, identity, and activation. Using RORA deficient iPSCs and pharmacologic interventions, we show that RORA is required for early differentiation and prevents diHSCs activation by reducing the high energetic state of the cells. While RORA knockout mice have enhanced fibrosis, RORA agonists rescue multi-organ fibrosis in in vivo models. Notably, RORA expression correlates negatively with liver fibrosis and HSCs activation markers in patients with liver disease. This study reveals that RORA regulates cell metabolic plasticity, important for mesoderm differentiation, pericyte quiescence, and fibrosis, influencing cell commitment and disease.
Suggested Citation
Raquel A. Martínez García de la Torre & Julia Vallverdú & Zhenqing Xu & Silvia Ariño & Raquel Ferrer-Lorente & Laura Zanatto & Maria Mercado-Gómez & Beatriz Aguilar-Bravo & Paloma Ruiz-Blázquez & Mari, 2025.
"Trajectory analysis of hepatic stellate cell differentiation reveals metabolic regulation of cell commitment and fibrosis,"
Nature Communications, Nature, vol. 16(1), pages 1-19, December.
Handle:
RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56024-4
DOI: 10.1038/s41467-025-56024-4
Download full text from publisher
Most related items
These are the items that most often cite the same works as this one and are cited by the same works as this one.
- Marie Bobowski-Gerard & Clémence Boulet & Francesco P. Zummo & Julie Dubois-Chevalier & Céline Gheeraert & Mohamed Bou Saleh & Jean-Marc Strub & Amaury Farce & Maheul Ploton & Loïc Guille & Jimmy Vand, 2022.
"Functional genomics uncovers the transcription factor BNC2 as required for myofibroblastic activation in fibrosis,"
Nature Communications, Nature, vol. 13(1), pages 1-20, December.
- Haushabhau S. Pagire & Suvarna H. Pagire & Byung-kwan Jeong & Won-Il Choi & Chang Joo Oh & Chae Won Lim & Minhee Kim & Jihyeon Yoon & Seong Soon Kim & Myung Ae Bae & Jae-Han Jeon & Sungmin Song & Hee , 2024.
"Discovery of a peripheral 5HT2A antagonist as a clinical candidate for metabolic dysfunction-associated steatohepatitis,"
Nature Communications, Nature, vol. 15(1), pages 1-12, December.
- Christian Freise & Hyunho Lee & Christopher Chronowski & Doug Chan & Jessica Cziomer & Martin Rühl & Tarkan Dagdelen & Maik Lösekann & Ulrike Erben & Andre Catic & Werner Tegge & Detlef Schuppan & Raj, 2021.
"Alpha-single chains of collagen type VI inhibit the fibrogenic effects of triple helical collagen VI in hepatic stellate cells,"
PLOS ONE, Public Library of Science, vol. 16(9), pages 1-18, September.
- Lu Han & Yongxia Wu & Kun Fang & Sean Sweeney & Ulyss K. Roesner & Melodie Parrish & Khushbu Patel & Tom Walter & Julia Piermattei & Anthony Trimboli & Julia Lefler & Cynthia D. Timmers & Xue-Zhong Yu, 2023.
"The splanchnic mesenchyme is the tissue of origin for pancreatic fibroblasts during homeostasis and tumorigenesis,"
Nature Communications, Nature, vol. 14(1), pages 1-12, December.
- Ming Yang & Xiaoqiang Qi & Nan Li & Jussuf T. Kaifi & Shiyou Chen & Andrew A. Wheeler & Eric T. Kimchi & Aaron C. Ericsson & R. Scott Rector & Kevin F. Staveley-O’Carroll & Guangfu Li, 2023.
"Western diet contributes to the pathogenesis of non-alcoholic steatohepatitis in male mice via remodeling gut microbiota and increasing production of 2-oleoylglycerol,"
Nature Communications, Nature, vol. 14(1), pages 1-17, December.
- Urban Lendahl & Lars Muhl & Christer Betsholtz, 2022.
"Identification, discrimination and heterogeneity of fibroblasts,"
Nature Communications, Nature, vol. 13(1), pages 1-14, December.
- Yuan Guan & Annika Enejder & Meiyue Wang & Zhuoqing Fang & Lu Cui & Shih-Yu Chen & Jingxiao Wang & Yalun Tan & Manhong Wu & Xinyu Chen & Patrik K. Johansson & Issra Osman & Koshi Kunimoto & Pierre Rus, 2021.
"A human multi-lineage hepatic organoid model for liver fibrosis,"
Nature Communications, Nature, vol. 12(1), pages 1-15, December.
- Sonal Sinha & Satoka Aizawa & Yasuhiro Nakano & Alexander Rialdi & Hye Yeon Choi & Rajan Shrestha & Stephanie Q. Pan & Yibu Chen & Meng Li & Audrey Kapelanski-Lamoureux & Gregory Yochum & Linda Sher &, 2023.
"Hepatic stellate cell stearoyl co-A desaturase activates leukotriene B4 receptor 2 - β-catenin cascade to promote liver tumorigenesis,"
Nature Communications, Nature, vol. 14(1), pages 1-14, December.
Corrections
All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56024-4. See general information about how to correct material in RePEc.
If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.
If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .
If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.
For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .
Please note that corrections may take a couple of weeks to filter through
the various RePEc services.