Dataset Information

TRAJECTORY ANALYSIS OF HEPATIC STELLATE CELL DIFFERENTIATION REVEALS METABOLIC REGULATION OF CELL COMMITMENT AND FIBROSIS

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 investigated the proteome trajectory of iPSCs differentiation to hepatic stellate cells (diHSCs) and identified RORA as a key transcription factor governing the metabolic reprogramming of HSCs necessary for HSCs’ commitment, identity, and activation. Using RORA deficient iPSCs and pharmacologic interventions, we showed that RORA is required for early differentiation and prevents diHSCs activation by reducing the high energetic state of the cells. While RORA knockout mice had enhanced fibrosis, whereas RORA agonists rescued multi-organ fibrosis in in vivo models. Notably, RORA expression was consistently found to be negatively correlated with liver fibrosis and HSCs activation markers in patients with liver disease. This study reveals that RORA regulates cell metabolic plasticity, crucial for mesoderm differentiation, pericyte quiescence, and fibrosis, influencing cell commitment and disease.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Mikel Azkargorta

LAB HEAD: Felix Elortza

PROVIDER: PXD058290 | Pride | 2025-05-07

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	PauS_10_MDJR17_4_Slot2-34_2-15-2020_6832.RAW	Raw
	PauS_11_MDJR17_6_Slot2-35_2-15-2020_6834.RAW	Raw
	PauS_12_MDJR17_8_Slot2-36_2-15-2020_6836.RAW	Raw
	PauS_13_MDJR17_10_Slot2-37_2-15-2020_6838.RAW	Raw
	PauS_14_MDJR17_12_Slot2-38_2-15-2020_6840.RAW	Raw

Items per page:

1 - 5 of 35

Publications

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

Martínez García de la Torre Raquel A RA Vallverdú Julia J Xu Zhenqing Z Ariño Silvia S Ferrer-Lorente Raquel R Zanatto Laura L Mercado-Gómez Maria M Aguilar-Bravo Beatriz B Ruiz-Blázquez Paloma P Fernandez-Fernandez Maria M Navarro-Gascon Artur A Blasco-Roset Albert A Sànchez-Fernàndez-de-Landa Paula P Pera Joan J Romero-Moya Damia D Ayuso Garcia Paula P Martínez Sánchez Celia C Sererols Viñas Laura L Cantallops Vilà Paula P Cárcamo Giráldez Carmen I CI McQuillin Andrew A Morgan Marsha Y MY Moya-Rull Daniel D Montserrat Núria N Eberlé Delphine D Staels Bart B Antoine Bénédicte B Azkargorta Mikel M Lozano Juan-José JJ Martínez-Chantar Maria L ML Giorgetti Alessandra A Elortza Félix F Planavila Anna A Varela-Rey Marta M Woodhoo Ashwin A Zorzano Antonio A Graupera Isabel I Moles Anna A Coll Mar M Affo Silvia S Sancho-Bru Pau P

Nature communications 20250210 1

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, ...[more]

PMID: 39929812

Similar Datasets

Project description:We employed CITE-Seq profiling of 62 277 high-quality FACS-enriched human bone marrow hematopoietic stem and progenitor cells (HSPCs) from 15 healthy donors representing young, mid and old age groups, using the BD Rhapsody platform. Our targeted gene panel consisting of 596 genes was supplemented with 46 cell-surface proteins to cover the most relevant markers of early HSPC differentiation and cell cycle status. We demonstrate a molecular map of early human hematopoietic stem cell (HSC) differentiation and provide evidence of early branching points into lineage trajectories across different age groups. Our data shows that the HSC branched into two main lineages, with the first branching point giving rise to megakaryocytic and erythroid progenitors (MKP/ERP), followed by lymphoid and myeloid progenitors (LMP/MDP). As expected, the most immature HSCs were defined by high expression of CD34, CD90, CRHBP, HOPX, HLF, MLLT3. Re-clustering and trajectory analysis of the most immature HSPCs confirmed early lineage commitment, suggesting that an MKP/ERP development does not include myeloid or lymphoid progenitors. A similar pattern was observed for all age groups. Interestingly, we observed increased expression of novel marker genes (HLA-E, DLK1, ADGRG6, and MMRN1) and the surface protein CD273/PD-L2 in the most immature HSCs. Besides a gradual upregulation of CD38 along differentiation, differentiated cells showed lower CD45 levels. tradeSeq analysis defined the continuous single cell expression changes in genes upon early differentiation and lineage commitment, allowing the detection of decision-making gene networks. Our data adds further evidence to a structured hierarchical organization of human hematopoiesis with a sequential loss of lineage potential, with the first branching point into the MEK/ERY lineage, and not an early commitment of uni-lineage restricted precursors. We report on the upregulation of ADGRG6, DLK1, HLA-E, MMRN1 and CD273 in the most immature HSCs. Functional experiments confirmed that CD273+ HSCs displayed the most quiescent profile with a high stemness signature as well as the immune-modulatory function of CD273+ on HSPCs in regulating T cell activation and cytokine release.