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Characterisation of a functional rat hepatocyte spheroid model.

Kyffin, JA, Sharma, P, Leedale, J, Colley, HE, Murdoch, C, Harding, AL, Mistry, P and Webb, SD (2018) Characterisation of a functional rat hepatocyte spheroid model. Toxicology In Vitro, 55. pp. 160-172. ISSN 0887-2333

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Abstract

Many in vitro liver cell models, such as 2D systems, that are used to assess the hepatotoxic potential of xenobiotics suffer major limitations arising from a lack of preservation of physiological phenotype and metabolic competence. To circumvent some of these limitations there has been increased focus on producing more representative 3D models. Here we have used a novel approach to construct a size-controllable 3D hepatic spheroid model using freshly isolated primary rat hepatocytes (PRH) utilising the liquid-overlay technique whereby PRH spontaneously self-assemble in to 3D microtissues. This system produces viable spheroids with a compact in vivo-like structure for up to 21 days with sustained albumin production for the duration of the culture period. F-actin was seen throughout the spheroid body and P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2) transporters had polarised expression on the canalicular membrane of hepatocytes within the spheroids upon formation (day 3). The MRP2 transporter was able to functionally transport 5 μM 5-chloromethylfluorescein diacetate (CMFDA) substrates into these canalicular structures. These PRH spheroids display in vivo characteristics including direct cell-cell contacts, cellular polarisation, 3D cellular morphology, and formation of functional secondary structures throughout the spheroid. Such a well-characterised system could be readily exploited for pre-clinical and non-clinical repeat-dose investigations and could make a significant contribution to replace, reduce and refine the use of animals for applied research.

Item Type: Article
Uncontrolled Keywords: 1115 Pharmacology And Pharmaceutical Sciences
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Applied Mathematics
Publisher: Elsevier
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Date Deposited: 08 Jan 2019 09:58
Last Modified: 08 Jan 2019 10:03
DOI or Identification number: 10.1016/j.tiv.2018.12.014
URI: http://researchonline.ljmu.ac.uk/id/eprint/9892

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