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Arch Toxicol. 2018 Oct;92(10):3117-3129. doi: 10.1007/s00204-018-2280-2. Epub 2018 Aug 28.

3D human liver tissue from pluripotent stem cells displays stable phenotype in vitro and supports compromised liver function in vivo.

Author information

1
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, EH16 4UU, UK.
2
Centre for Liver Research, Institute of Immunology and Immunotherapy and National Institute for Health Research Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, UK.
3
Institute of Bioengineering, The University of Edinburgh, King's Buildings, Edinburgh, EH9 3DW, UK.
4
School of Chemistry, University of Edinburgh, Kings Buildings, EH9 3FJ, Edinburgh, UK.
5
Anne McLaren Laboratory, Wellcome Trust-MRC Stem Cell Institute, University of Cambridge, Cambridge, CB2 0SZ, UK.
6
Child Health Clinical Academic Group, MRC Centre for Transplantation, King's College London, London, UK.
7
Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
8
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, EH16 4UU, UK. davehay@talktalk.net.

Abstract

Liver disease is an escalating global health issue. While liver transplantation is an effective mode of therapy, patient mortality has increased due to the shortage of donor organs. Developing renewable sources of human liver tissue is therefore attractive. Pluripotent stem cell-derived liver tissue represents a potential alternative to cadaver derived hepatocytes and whole organ transplant. At present, two-dimensional differentiation procedures deliver tissue lacking certain functions and long-term stability. Efforts to overcome these limiting factors have led to the building of three-dimensional (3D) cellular aggregates. Although enabling for the field, their widespread application is limited due to their reliance on variable biological components. Our studies focused on the development of 3D liver tissue under defined conditions. In vitro generated 3D tissues exhibited stable phenotype for over 1 year in culture, providing an attractive resource for long-term in vitro studies. Moreover, 3D derived tissue provided critical liver support in two animal models, including immunocompetent recipients. Therefore, we believe that our study provides stable human tissue to better model liver biology 'in the dish', and in the future may permit the support of compromised liver function in humans.

KEYWORDS:

Implantable liver graft; Interdisciplinary research; Liver tissue; Pluripotent stem cell; Stable cell phenotype

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