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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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE282539 | GEO | 2025/01/03

REPOSITORIES: GEO

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Project description:During chronic liver disease, tissue remodeling leads to dramatic changes and accumulation of matrix components. Matrix metalloproteases and their inhibitors have been involved in the regulation of matrix degradation. However, the role of other proteases remains incompletely defined. We undertook a gene-expression screen of human liver fibrosis samples using a dedicated gene array selected for relevance to protease activities, identifying the ADAMTS1 (A Disintegrin And Metalloproteinase [ADAM] with thrombospondin type 1 motif, 1) gene as an important node of the protease network. Up-regulation of ADAMTS1 in fibrosis was found to be associated with hepatic stellate cell (HSC) activation. ADAMTS1 is synthesized as 110-kDa latent forms and is processed by HSCs to accumulate as 87-kDa mature forms in fibrotic tissues. Structural evidence has suggested that the thrombospondin motif-containing domain from ADAMTS1 may be involved in interactions with, and activation of, the major fibrogenic cytokine, transforming growth factor beta (TGF-β). Indeed, we observed direct interactions between ADAMTS1 and latency-associated peptide-TGF-β (LAP-TGF-β). ADAMTS1 induces TGF-β activation through the interaction of the ADAMTS1 KTFR peptide with the LAP-TGF-β LKSL peptide. Down-regulation of ADAMTS1 in HSCs decreases the release of TGF-β competent for transcriptional activation, and KTFR competitor peptides directed against ADAMTS1 block the HSC-mediated release of active TGF-β. Using a mouse liver fibrosis model, we show that carbon tetrachloride treatment induces ADAMTS1 expression in parallel to that of type I collagen. Importantly, concurrent injection of the KTFR peptide prevents liver damage. CONCLUSION: Our results indicate that up-regulation of ADAMTS1 in HSCs constitutes a new mechanism for control of TGF-β activation in chronic liver disease. Total RNA from 32 patients with hepatic fibrosis associated with hepatitis C virus (HCV) infection (n=15) or alcohol abuse (n=17) versus a common pooled control liver sample, inverting the cy3 and cy5 labelling for each sample.

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

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