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Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease

Liver biology and function, drug-induced liver injury (DILI) and liver diseases are difficult to study using current in vitro models such as primary human hepatocyte (PHH) monolayer cultures, as their rapid de-differentiation restricts their usefulness substantially. Thus, we have developed and exte...

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Autores principales: Bell, Catherine C., Hendriks, Delilah F. G., Moro, Sabrina M. L., Ellis, Ewa, Walsh, Joanne, Renblom, Anna, Fredriksson Puigvert, Lisa, Dankers, Anita C. A., Jacobs, Frank, Snoeys, Jan, Sison-Young, Rowena L., Jenkins, Rosalind E., Nordling, Åsa, Mkrtchian, Souren, Park, B. Kevin, Kitteringham, Neil R., Goldring, Christopher E. P., Lauschke, Volker M., Ingelman-Sundberg, Magnus
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855186/
https://www.ncbi.nlm.nih.gov/pubmed/27143246
http://dx.doi.org/10.1038/srep25187
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author Bell, Catherine C.
Hendriks, Delilah F. G.
Moro, Sabrina M. L.
Ellis, Ewa
Walsh, Joanne
Renblom, Anna
Fredriksson Puigvert, Lisa
Dankers, Anita C. A.
Jacobs, Frank
Snoeys, Jan
Sison-Young, Rowena L.
Jenkins, Rosalind E.
Nordling, Åsa
Mkrtchian, Souren
Park, B. Kevin
Kitteringham, Neil R.
Goldring, Christopher E. P.
Lauschke, Volker M.
Ingelman-Sundberg, Magnus
author_facet Bell, Catherine C.
Hendriks, Delilah F. G.
Moro, Sabrina M. L.
Ellis, Ewa
Walsh, Joanne
Renblom, Anna
Fredriksson Puigvert, Lisa
Dankers, Anita C. A.
Jacobs, Frank
Snoeys, Jan
Sison-Young, Rowena L.
Jenkins, Rosalind E.
Nordling, Åsa
Mkrtchian, Souren
Park, B. Kevin
Kitteringham, Neil R.
Goldring, Christopher E. P.
Lauschke, Volker M.
Ingelman-Sundberg, Magnus
author_sort Bell, Catherine C.
collection PubMed
description Liver biology and function, drug-induced liver injury (DILI) and liver diseases are difficult to study using current in vitro models such as primary human hepatocyte (PHH) monolayer cultures, as their rapid de-differentiation restricts their usefulness substantially. Thus, we have developed and extensively characterized an easily scalable 3D PHH spheroid system in chemically-defined, serum-free conditions. Using whole proteome analyses, we found that PHH spheroids cultured this way were similar to the liver in vivo and even retained their inter-individual variability. Furthermore, PHH spheroids remained phenotypically stable and retained morphology, viability, and hepatocyte-specific functions for culture periods of at least 5 weeks. We show that under chronic exposure, the sensitivity of the hepatocytes drastically increased and toxicity of a set of hepatotoxins was detected at clinically relevant concentrations. An interesting example was the chronic toxicity of fialuridine for which hepatotoxicity was mimicked after repeated-dosing in the PHH spheroid model, not possible to detect using previous in vitro systems. Additionally, we provide proof-of-principle that PHH spheroids can reflect liver pathologies such as cholestasis, steatosis and viral hepatitis. Combined, our results demonstrate that the PHH spheroid system presented here constitutes a versatile and promising in vitro system to study liver function, liver diseases, drug targets and long-term DILI.
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spelling pubmed-48551862016-05-18 Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease Bell, Catherine C. Hendriks, Delilah F. G. Moro, Sabrina M. L. Ellis, Ewa Walsh, Joanne Renblom, Anna Fredriksson Puigvert, Lisa Dankers, Anita C. A. Jacobs, Frank Snoeys, Jan Sison-Young, Rowena L. Jenkins, Rosalind E. Nordling, Åsa Mkrtchian, Souren Park, B. Kevin Kitteringham, Neil R. Goldring, Christopher E. P. Lauschke, Volker M. Ingelman-Sundberg, Magnus Sci Rep Article Liver biology and function, drug-induced liver injury (DILI) and liver diseases are difficult to study using current in vitro models such as primary human hepatocyte (PHH) monolayer cultures, as their rapid de-differentiation restricts their usefulness substantially. Thus, we have developed and extensively characterized an easily scalable 3D PHH spheroid system in chemically-defined, serum-free conditions. Using whole proteome analyses, we found that PHH spheroids cultured this way were similar to the liver in vivo and even retained their inter-individual variability. Furthermore, PHH spheroids remained phenotypically stable and retained morphology, viability, and hepatocyte-specific functions for culture periods of at least 5 weeks. We show that under chronic exposure, the sensitivity of the hepatocytes drastically increased and toxicity of a set of hepatotoxins was detected at clinically relevant concentrations. An interesting example was the chronic toxicity of fialuridine for which hepatotoxicity was mimicked after repeated-dosing in the PHH spheroid model, not possible to detect using previous in vitro systems. Additionally, we provide proof-of-principle that PHH spheroids can reflect liver pathologies such as cholestasis, steatosis and viral hepatitis. Combined, our results demonstrate that the PHH spheroid system presented here constitutes a versatile and promising in vitro system to study liver function, liver diseases, drug targets and long-term DILI. Nature Publishing Group 2016-05-04 /pmc/articles/PMC4855186/ /pubmed/27143246 http://dx.doi.org/10.1038/srep25187 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Bell, Catherine C.
Hendriks, Delilah F. G.
Moro, Sabrina M. L.
Ellis, Ewa
Walsh, Joanne
Renblom, Anna
Fredriksson Puigvert, Lisa
Dankers, Anita C. A.
Jacobs, Frank
Snoeys, Jan
Sison-Young, Rowena L.
Jenkins, Rosalind E.
Nordling, Åsa
Mkrtchian, Souren
Park, B. Kevin
Kitteringham, Neil R.
Goldring, Christopher E. P.
Lauschke, Volker M.
Ingelman-Sundberg, Magnus
Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease
title Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease
title_full Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease
title_fullStr Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease
title_full_unstemmed Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease
title_short Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease
title_sort characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855186/
https://www.ncbi.nlm.nih.gov/pubmed/27143246
http://dx.doi.org/10.1038/srep25187
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