Hepatocyte Thorns, A Novel Drug-Induced Stress Response in Human and Mouse Liver Spheroids
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...
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MDPI AG
2022-05-01
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| Online Access: | https://www.mdpi.com/2073-4409/11/10/1597 |
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| author | Chris S. Pridgeon Dian P. Bolhuis Filip Milosavljević Marina Manojlović Ákos Végvári Massimiliano Gaetani Marin M. Jukić Magnus Ingelman-Sundberg |
| author_facet | Chris S. Pridgeon Dian P. Bolhuis Filip Milosavljević Marina Manojlović Ákos Végvári Massimiliano Gaetani Marin M. Jukić Magnus Ingelman-Sundberg |
| author_sort | Chris S. Pridgeon |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T03:10:31Z |
| format | Article |
| id | doaj.art-4c4174d7996a465686fdc413f7be0eef |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T03:10:31Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-4c4174d7996a465686fdc413f7be0eef2023-11-23T10:26:56ZengMDPI AGCells2073-44092022-05-011110159710.3390/cells11101597Hepatocyte Thorns, A Novel Drug-Induced Stress Response in Human and Mouse Liver SpheroidsChris S. Pridgeon0Dian P. Bolhuis1Filip Milosavljević2Marina Manojlović3Ákos Végvári4Massimiliano Gaetani5Marin M. Jukić6Magnus Ingelman-Sundberg7Department of Physiology and Pharmacology, Karolinska Institutet, 171 65 Stockholm, SwedenDepartment of Physiology and Pharmacology, Karolinska Institutet, 171 65 Stockholm, SwedenFaculty of Pharmacy, University of Belgrade, 11221 Belgrade, SerbiaFaculty of Pharmacy, University of Belgrade, 11221 Belgrade, SerbiaProteomics Biomedicum, Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, SwedenChemical Proteomics, Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, SwedenDepartment of Physiology and Pharmacology, Karolinska Institutet, 171 65 Stockholm, SwedenDepartment of Physiology and Pharmacology, Karolinska Institutet, 171 65 Stockholm, SwedenThe 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.https://www.mdpi.com/2073-4409/11/10/1597hepatocytesspheroidsthornshepatotoxicitykeratins3D culture |
| spellingShingle | Chris S. Pridgeon Dian P. Bolhuis Filip Milosavljević Marina Manojlović Ákos Végvári Massimiliano Gaetani Marin M. Jukić Magnus Ingelman-Sundberg Hepatocyte Thorns, A Novel Drug-Induced Stress Response in Human and Mouse Liver Spheroids Cells hepatocytes spheroids thorns hepatotoxicity keratins 3D culture |
| title | Hepatocyte Thorns, A Novel Drug-Induced Stress Response in Human and Mouse Liver Spheroids |
| title_full | Hepatocyte Thorns, A Novel Drug-Induced Stress Response in Human and Mouse Liver Spheroids |
| title_fullStr | Hepatocyte Thorns, A Novel Drug-Induced Stress Response in Human and Mouse Liver Spheroids |
| title_full_unstemmed | Hepatocyte Thorns, A Novel Drug-Induced Stress Response in Human and Mouse Liver Spheroids |
| title_short | Hepatocyte Thorns, A Novel Drug-Induced Stress Response in Human and Mouse Liver Spheroids |
| title_sort | hepatocyte thorns a novel drug induced stress response in human and mouse liver spheroids |
| topic | hepatocytes spheroids thorns hepatotoxicity keratins 3D culture |
| url | https://www.mdpi.com/2073-4409/11/10/1597 |
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