An In Vitro Whole-Organ Liver Engineering for Testing of Genetic Therapies
Maëlle Lorvellec,
Alessandro Filippo Pellegata,
Alice Maestri,
Chiara Turchetta,
Elena Alvarez Mediavilla,
Soichi Shibuya,
Brendan Jones,
Federico Scottoni,
Dany P. Perocheau,
Andrei Claudiu Cozmescu,
Juliette M. Delhove,
Daniel Kysh,
Asllan Gjinovci,
John R. Counsell,
Wendy E. Heywood,
Kevin Mills,
Tristan R. McKay,
Paolo De Coppi,
Paul Gissen
Affiliations
Maëlle Lorvellec
MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK; Genetics and Genomic Medicine Department, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK; Corresponding author
Alessandro Filippo Pellegata
Developmental Biology and Cancer Research & Teaching Department, Stem Cells & Regenerative Medicine Section, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK
Alice Maestri
MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK; Genetics and Genomic Medicine Department, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK
Chiara Turchetta
Department of Chemistry, Materials and Chemical Engineering ''Giulio Natta,'' Politecnico di Milano, Milan 20133, Italy
Elena Alvarez Mediavilla
Genetics and Genomic Medicine Department, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK
Soichi Shibuya
Developmental Biology and Cancer Research & Teaching Department, Stem Cells & Regenerative Medicine Section, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK
Brendan Jones
Developmental Biology and Cancer Research & Teaching Department, Stem Cells & Regenerative Medicine Section, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK
Federico Scottoni
Developmental Biology and Cancer Research & Teaching Department, Stem Cells & Regenerative Medicine Section, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK
Dany P. Perocheau
Genetics and Genomic Medicine Department, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK
Andrei Claudiu Cozmescu
MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK; NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London WC1N 1EH, UK
Juliette M. Delhove
Robinson Research Institute, University of Adelaide, Adelaide, SA, 5006, Australia
Daniel Kysh
MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK
Asllan Gjinovci
MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK
John R. Counsell
Dubowitz Neuromuscular Centre, Molecular Neurosciences Section, Developmental Neurosciences Programme, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK
Wendy E. Heywood
Genetics and Genomic Medicine Department, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK
Kevin Mills
Genetics and Genomic Medicine Department, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK
Tristan R. McKay
Centre for Bioscience, Manchester Metropolitan University, Manchester M1 5GD, UK
Paolo De Coppi
Developmental Biology and Cancer Research & Teaching Department, Stem Cells & Regenerative Medicine Section, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK
Paul Gissen
MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK; Genetics and Genomic Medicine Department, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK
Summary: Explosion of gene therapy approaches for treating rare monogenic and common liver disorders created an urgent need for disease models able to replicate human liver cellular environment. Available models lack 3D liver structure or are unable to survive in long-term culture. We aimed to generate and test a 3D culture system that allows long-term maintenance of human liver cell characteristics.The in vitro whole-organ “Bioreactor grown Artificial Liver Model” (BALM) employs a custom-designed bioreactor for long-term 3D culture of human induced pluripotent stem cells-derived hepatocyte-like cells (hiHEPs) in a mouse decellularized liver scaffold. Adeno-associated viral (AAV) and lentiviral (LV) vectors were introduced by intravascular injection.Substantial AAV and LV transgene expression in the BALM-grown hiHEPs was detected. Measurement of secreted proteins in the media allowed non-invasive monitoring of the system.We demonstrated that humanized whole-organ BALM is a valuable tool to generate pre-clinical data for investigational medicinal products.
