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

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, Maria Fernandez- Fernandez, Artur Navarro-Gascon, Albert Blasco-Roset, Paula Sànchez-Fernàndez- de-Landa, Joan Pera, Damia Romero-Moya, Paula Ayuso Garcia, Celia Martínez Sánchez, Laura Sererols Viñas, Paula Cantallops Vilà, Carmen I. Cárcamo Giráldez, Andrew McQuillin, Marsha Y. Morgan, Daniel Moya-Rull, Núria Montserrat, Delphine Eberlé, Bart Staels, Bénédicte Antoine, Mikel Azkargorta, Juan-José Lozano, Maria L. Martínez-Chantar, Alessandra Giorgetti, Félix Elortza, Anna Planavila, Marta Varela-Rey, Ashwin Woodhoo, Antonio Zorzano, Isabel Graupera, Anna Moles, Mar Coll, Silvia Affo () and Pau Sancho-Bru ()
Additional contact information
Raquel A. Martínez García de la Torre: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Julia Vallverdú: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Zhenqing Xu: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Silvia Ariño: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Raquel Ferrer-Lorente: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Laura Zanatto: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
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)
Maria Fernandez- Fernandez: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Artur Navarro-Gascon: Universitat de Barcelona
Albert Blasco-Roset: Universitat de Barcelona
Paula Sànchez-Fernàndez- de-Landa: Universitat de Barcelona
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)
Laura Sererols Viñas: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Paula Cantallops Vilà: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
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)
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)
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)
Alessandra Giorgetti: Institut d’Investigació Biomèdica de Bellvitge (IDIBELL)
Félix Elortza: Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)
Anna Planavila: Universitat de Barcelona
Marta Varela-Rey: University of Santiago de Compostela
Ashwin Woodhoo: University of Santiago de Compostela
Antonio Zorzano: Universitat de Barcelona
Isabel Graupera: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Anna Moles: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Mar Coll: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Silvia Affo: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Pau Sancho-Bru: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56024-4

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