Trajectory analysis of hepatic stellate cell differentiation reveals metabolic regulation of cell commitment and fibrosis.
Por:
Martínez García de la Torre RA, Vallverdú J, Xu Z, Ariño S, Ferrer-Lorente R, Zanatto L, Mercado-Gómez M, Aguilar-Bravo B, Ruiz-Blázquez P, Fernandez-Fernandez M, Navarro-Gascon A, Blasco-Roset A, Sànchez-Fernàndez-de-Landa P, Pera J, Romero-Moya D, Ayuso Garcia P, Martínez Sánchez C, Sererols Viñas L, Cantallops Vilà P, Cárcamo Giráldez CI, McQuillin A, Morgan MY, Moya-Rull D, Montserrat N, Eberlé D, Staels B, Antoine B, Azkargorta M, Lozano JJ, Martínez-Chantar ML, Giorgetti A, Elortza F, Planavila A, Varela-Rey M, Woodhoo A, Zorzano A, Graupera I, Moles A, Coll M, Affo S and Sancho-Bru P
Publicada:
10 feb 2025
Ahead of Print:
10 feb 2025
Resumen:
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.
Filiaciones:
Martínez García de la Torre RA:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
University of Barcelona, Barcelona, Spain
Vallverdú J:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Xu Z:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
University of Barcelona, Barcelona, Spain
Ariño S:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
University of Barcelona, Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain
Ferrer-Lorente R:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Zanatto L:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
University of Barcelona, Barcelona, Spain
Mercado-Gómez M:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Aguilar-Bravo B:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Ruiz-Blázquez P:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
University of Barcelona, Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain
Department of Experimental Pathology, Institute of Biomedical Research of Barcelona, Spanish National Research Council (IIBB-CSIC), Barcelona, Spain
Fernandez-Fernandez M:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
University of Barcelona, Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain
Department of Experimental Pathology, Institute of Biomedical Research of Barcelona, Spanish National Research Council (IIBB-CSIC), Barcelona, Spain
Navarro-Gascon A:
Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Institut de Biomedicina de la Universitat de Barcelona, Universitat de Barcelona, Barcelona, Spain
CIBER Fisitopatologia de la Obesidad y Nutrición, Instituto de Salud Carlos III, Barcelona, Spain
Blasco-Roset A:
Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Institut de Biomedicina de la Universitat de Barcelona, Universitat de Barcelona, Barcelona, Spain
CIBER Fisitopatologia de la Obesidad y Nutrición, Instituto de Salud Carlos III, Barcelona, Spain
Sànchez-Fernàndez-de-Landa P:
Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Institut de Biomedicina de la Universitat de Barcelona, Universitat de Barcelona, Barcelona, Spain
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
:
Regenerative Medicine Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain
Romero-Moya D:
Regenerative Medicine Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain
Ayuso Garcia P:
Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, Santiago de Compostela, Spain
Martínez Sánchez C:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
University of Barcelona, Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain
Sererols Viñas L:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
University of Barcelona, Barcelona, Spain
Cantallops Vilà P:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
University of Barcelona, Barcelona, Spain
Cárcamo Giráldez CI:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
McQuillin A:
Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, WC1E 6DE, UK
Morgan MY:
UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, NW3 2PF, UK
Moya-Rull D:
Pluripotency for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), Barcelona Institute of Science and Technology (BIST), Carrer de Baldiri i Reixac, 15-21, Barcelona, Spain
Montserrat N:
Pluripotency for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), Barcelona Institute of Science and Technology (BIST), Carrer de Baldiri i Reixac, 15-21, Barcelona, Spain
Catalan Institute for Research and Advanced Studies (ICREA), Passeig de Lluís Companys 23, Barcelona, Spain
Eberlé D:
Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, 59000, Lille, France
Staels B:
Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, 59000, Lille, France
Antoine B:
Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, F-75012, Paris, France
Azkargorta M:
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain
Proteomics Platform, CIC BioGUNE, Basque Research and Technology Alliance (BRTA), Bizkaia Science and Technology Park, Derio, Spain
Lozano JJ:
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain
Martínez-Chantar ML:
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain
Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, Derio, Spain
Giorgetti A:
Regenerative Medicine Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain
Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Barcelona University, Barcelona, Spain
Elortza F:
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain
Proteomics Platform, CIC BioGUNE, Basque Research and Technology Alliance (BRTA), Bizkaia Science and Technology Park, Derio, Spain
Planavila A:
Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Institut de Biomedicina de la Universitat de Barcelona, Universitat de Barcelona, Barcelona, Spain
CIBER Fisitopatologia de la Obesidad y Nutrición, Instituto de Salud Carlos III, Barcelona, Spain
Varela-Rey M:
Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, Santiago de Compostela, Spain
Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Barcelona University, Barcelona, Spain
Woodhoo A:
Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, Santiago de Compostela, Spain
Department of Biochemistry and Molecular Biology, University of Santiago de Compostela, Plaza do Obradoiro s/n, Santiago de Compostela, Spain
Oportunius Research Professor at CIMUS/USC, Galician Agency of Innovation (GAIN), Xunta de Galicia, Santiago de Compostela, A Coruña, Spain
Zorzano A:
Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Institut de Biomedicina de la Universitat de Barcelona, Universitat de Barcelona, Barcelona, Spain
CIBER Fisitopatologia de la Obesidad y Nutrición, Instituto de Salud Carlos III, Barcelona, Spain
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, 28029, Madrid, Spain
Graupera I:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain
Liver Unit, Hospital Clínic, Faculty of Medicine, University of Barcelona, Barcelona, Spain
Moles A:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain
Department of Experimental Pathology, Institute of Biomedical Research of Barcelona, Spanish National Research Council (IIBB-CSIC), Barcelona, Spain
Coll M:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
University of Barcelona, Barcelona, Spain
Medicine Department, Faculty of Medicine, University of Barcelona, Barcelona, Spain
Affo S:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Sancho-Bru P:
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain
Medicine Department, Faculty of Medicine, University of Barcelona, Barcelona, Spain
Open Access
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