Improved Translational Relevance of In Vitro Fibrosis Models by Integrating IOX2-Mediated Hypoxia-Mimicking Pathways
article
Background/Objectives: Preclinical models of liver fibrosis only partially mimic human disease processes. Particularly, traditional transforming growth factor beta 1 (TGFβ1)-induced hepatic stellate cell (HSC) models lack relevant processes, including hypoxia-induced pathways. Here, the ability of a hypoxia-mimicking compound (IOX2) to more accurately reflect the human fibrotic phenotype on a functional level was investigated. Methods: Human primary HSCs were stimulated (TGFβ1 +/- IOX2), and the cell viability and fibrotic phenotype were determined. The latter was assessed as protein levels of fibrosis markers-collagen, TIMP-1, and Fibronectin. Next-generation sequencing (NGS), differential expression analyses (DESeq2), and Ingenuity Pathway Analysis (IPA) were performed for mechanistic evaluation and biological annotation. Results: Stimulation with TGFβ1 + IOX2 significantly increased fibrotic marker levels. Also, fibrosis-related pathways were activated, and hypoxia-related genes and collagen modifications, such as crosslinking, increased dose-dependently. Comparative analysis with human fibrotic DEGs showed improved disease representation in the HSC model in the presence of IOX2. Conclusions: In conclusion, the HSC model better recapitulated liver fibrosis by IOX2 administration. Therefore, hypoxia-mimicking compounds hold promise for enhancing the translational value of in vitro fibrosis models, providing valuable insights in liver fibrosis pathogenesis and potential therapeutic strategies
TNO Identifier
1015323
Source
Biomedicines, 13(6)
Article nr.
1448