NDLI: Hepatocyte Thorns, A Novel Drug-Induced Stress Response in Human and Mouse Liver Spheroids

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Hepatocyte Thorns, A Novel Drug-Induced Stress Response in Human and Mouse Liver Spheroids

Content Provider	MDPI
Author	Filip, Milosavljević Marina, Manojlović Marin, M. Jukić Végvári, Ákos Pridgeon, Chris S. Bolhuis, Dian P. Gaetani, Massimiliano Ingelman-Sundberg, Magnus
Copyright Year	2022
Description	The in vivo-relevant phenotype of 3D liver spheroids allows for long-term studies of, e.g., novel mechanisms of chronic drug-induced liver toxicity. Using this system, we present a novel drug-induced stress response in human and murine hepatocyte spheroids, wherein long slender filaments form after chronic treatment with four different drugs, of which three are PPARα antagonists. The morphology of the thorns varies between donors and the compounds used. They are mainly composed of diverse protein fibres, which are glycosylated. Their formation is inhibited by treatment with fatty acids or antioxidants. Treatment of mice with GW6471 revealed changes in gene and protein expression, such as those in the spheroids. In addition, similar changes in keratin expression were seen following the treatment of hepatotoxic drugs, including aflatoxin B1, paracetamol, chlorpromazine, cyclosporine, and ketoconazole. We suggest that thorn formation may be indicative of hepatocyte metaplasia in response to toxicity and that more focus should be placed on alterations of ECM-derived protein expression as biomarkers of liver disease and chronic drug-induced hepatotoxicity, changes that can be studied in stable in vivo-like hepatic cell systems, such as the spheroids.
Starting Page	1597
e-ISSN	20734409
DOI	10.3390/cells11101597
Journal	Cells
Issue Number	10
Volume Number	11
Language	English
Publisher	MDPI
Publisher Date	2022-05-10
Access Restriction	Open
Subject Keyword	Cells Toxicology Hepatocytes Spheroids Thorns Hepatotoxicity Keratins 3d Culture
Content Type	Text
Resource Type	Article

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