TY  - JOUR
AU  - Pridgeon, Chris
AU  - Bolhuis, Dian
AU  - Milosavljević, Filip
AU  - Manojlović, Marina
AU  - Végvári, Ákos
AU  - Gaetani, Massimiliano
AU  - Jukić, Marin
AU  - Ingelman-Sundberg, Magnus
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4111
AB  - 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.
PB  - MDPI
T2  - Cells
T1  - Hepatocyte Thorns, A Novel Drug-Induced Stress Response in Human and Mouse Liver Spheroids
VL  - 11
IS  - 10
DO  - 10.3390/cells11101597
ER  - 

@article{
author = "Pridgeon, Chris and Bolhuis, Dian and Milosavljević, Filip and Manojlović, Marina and Végvári, Ákos and Gaetani, Massimiliano and Jukić, Marin and Ingelman-Sundberg, Magnus",
year = "2022",
abstract = "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.",
publisher = "MDPI",
journal = "Cells",
title = "Hepatocyte Thorns, A Novel Drug-Induced Stress Response in Human and Mouse Liver Spheroids",
volume = "11",
number = "10",
doi = "10.3390/cells11101597"
}

Pridgeon, C., Bolhuis, D., Milosavljević, F., Manojlović, M., Végvári, Á., Gaetani, M., Jukić, M.,& Ingelman-Sundberg, M.. (2022). Hepatocyte Thorns, A Novel Drug-Induced Stress Response in Human and Mouse Liver Spheroids. in Cells
MDPI., 11(10).
https://doi.org/10.3390/cells11101597

Pridgeon C, Bolhuis D, Milosavljević F, Manojlović M, Végvári Á, Gaetani M, Jukić M, Ingelman-Sundberg M. Hepatocyte Thorns, A Novel Drug-Induced Stress Response in Human and Mouse Liver Spheroids. in Cells. 2022;11(10).
doi:10.3390/cells11101597 .

Pridgeon, Chris, Bolhuis, Dian, Milosavljević, Filip, Manojlović, Marina, Végvári, Ákos, Gaetani, Massimiliano, Jukić, Marin, Ingelman-Sundberg, Magnus, "Hepatocyte Thorns, A Novel Drug-Induced Stress Response in Human and Mouse Liver Spheroids" in Cells, 11, no. 10 (2022),
https://doi.org/10.3390/cells11101597 . .