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 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

SUBMITTER: Martinez Garcia de la Torre RA 

PROVIDER: S-EPMC11811062 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature