Improved Translational Relevance of In Vitro Fibrosis Models by Integrating IOX2-Mediated Hypoxia-Mimicking Pathways

Improved Translational Relevance of In Vitro Fibrosis Models by Integrating IOX2-Mediated Hypoxia-Mimicking Pathways

<b>Background/Objectives</b>: 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. Her...

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Main Authors: Manuel A. González Hernández, Jennifer Venhorst, Lars Verschuren, Karin Toet, Martien P. M. Caspers, Martine C. Morrison, Beatrice Coornaert, Gerard J. P. van Westen, Roeland Hanemaaijer
Format: Article
Language:English
Published: MDPI AG 2025-06-01
Series:Biomedicines
Subjects:
liver fibrosis
preclinical models
fibrosis mechanisms
hypoxia
Online Access:https://www.mdpi.com/2227-9059/13/6/1448
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Summary:<b>Background/Objectives</b>: 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. <b>Methods</b>: 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. <b>Results</b>: 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. <b>Conclusions</b>: 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.
ISSN:2227-9059

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