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Trajectory analysis of hepatic stellate cell differentiation reveals metabolic regulation of cell commitment and fibrosis

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
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    References listed on IDEAS

    as
    1. Ingmar Mederacke & Christine C. Hsu & Juliane S. Troeger & Peter Huebener & Xueru Mu & Dianne H. Dapito & Jean-Philippe Pradere & Robert F. Schwabe, 2013. "Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology," Nature Communications, Nature, vol. 4(1), pages 1-11, December.
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