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

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.

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Publication Details

Journal
Nature Communications
Published
2025-02-10
DOI
https://doi.org/10.1038/s41467-025-56024-4
Citations
11
Primary Topic
Liver Disease Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
14.90

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article

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

Bart Staels, Paula Sànchez‐Fernàndez‐de‐Landa, Alessandra Giorgetti, Ashwin Woodhoo et al.
11 citations
Nature Communications
Liver Disease Diagnosis and Treatment
14.90
article

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

Bart Staels, Paula Sànchez‐Fernàndez‐de‐Landa, Alessandra Giorgetti, Ashwin Woodhoo, Damià Romero–Moya, Daniel Moya-Rull, Celia Martínez–Sánchez, Albert Blasco‐Roset, Raquel A. Martinez García de la Torre, Artur Navarro‐Gascon, Juan José Lozano, Pau Sancho‐Bru, Núria Montserrat, María Mercado-Gómez, Anna Planavila, Isabel Graupera, Beatriz Aguilar‐Bravo, Félix Elortza, Laura Zanatto, Marta Varela‐Rey, Delphine Eberlé, Sílvia Ariño, António Zorzano, Andrew McQuillin, Paula Cantallops Vilà, Anna Moles, Mar Coll, Marsha Y. Morgan, Maria Luz Martínez‐Chantar, Mikel Azkargorta, M. Guadalupe Fernández, Paloma Ruiz-Blázquez, Júlia Vallverdú, Silvia Affò, Raquel Ferrer‐Lorente, Zhixin Xu, Bénédicte Antoine, Joan Pera, Laura Sererols Viñas, Paula Ayuso Garcia, Carmen I. Cárcamo Giráldez
article en
11 citations

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.

Nature CommunicationsVol. 16(1)
Institució Catalana de Recerca i Estudis Avançats (ES), Inserm (FR), Universidade de Santiago de Compostela (ES), Université de Lille (FR), Xunta de Galicia (ES), Institut Pasteur de Lille (FR), The Royal Free Hospital (GB), Instituto de Salud Carlos III (ES), Centre Hospitalier Universitaire de Lille (FR), Sorbonne Université (FR), Institut d'Investigació Biomédica de Bellvitge (ES), Euskadiko Parke Teknologikoa (ES), Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (ES), Center for Research in Molecular Medicine and Chronic Diseases (ES), CIC bioGUNE (ES), Institute for Research in Biomedicine (ES), Institut d'Investigacions Biomèdiques de Barcelona (ES), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (ES), Centre de Recherche Saint-Antoine (FR), Institute for Bioengineering of Catalonia (ES), Instituto de Investigación Sanitaria de Santiago (ES), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), University College London (GB), Universitat de Barcelona (ES)
Pfizer, “la Caixa” Foundation, Centres de Recerca de Catalunya, European Commission, Generalitat de Catalunya, Ministerio de Educación, Cultura y Deporte, Ministerio de Ciencia e Innovación, José Carreras Leukämie-Stiftung, Horizon 2020 Framework Programme, Agència de Gestió d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III, Agencia Estatal de Investigación
Openalex Percentile: Top 1%
Liver Disease Diagnosis and Treatment
14.90
DOIOpen Access PDFOpenAlex
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