An In Vitro Whole-Organ Liver Engineering for Testing of Genetic Therapies

• Published in: iScience Vol. 23; no. 12; p. 101808
• Main Authors: Lorvellec, Maëlle, Pellegata, Alessandro Filippo, Maestri, Alice, Turchetta, Chiara, Alvarez Mediavilla, Elena, Shibuya, Soichi, Jones, Brendan, Scottoni, Federico, Perocheau, Dany P., Cozmescu, Andrei Claudiu, Delhove, Juliette M., Kysh, Daniel, Gjinovci, Asllan, Counsell, John R., Heywood, Wendy E., Mills, Kevin, McKay, Tristan R., De Coppi, Paolo, Gissen, Paul
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.12.2020; Elsevier
• Subjects: Bioengineering; Clinical Genetics; Medicin och hälsovetenskap; Tissue Engineering; Bioengineering; Clinical Genetics; Tissue Engineering
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2020.101808

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. [Display omitted] •Generation of a perfused humanized in vitro whole liver bioreactor model: BALM•BALM improves maturation and long-term survival of human iPS-derived hepatocytes•BALM allows viral transduction of human iHEPs through its vasculature•BALM provides a tool for gene therapy testing of human iHEPs Clinical Genetics; Bioengineering; Tissue Engineering