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 knockoutmice 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.