Biofabrication of synthetic human liver tissue with advanced programmable functions.

Autor:	Florentino RM; Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, USA., Morita K; Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA., Haep N; Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA., Motomura T; Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA., Diaz-Aragon R; Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA., Faccioli LAP; Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA., Collin de l'Hortet A; Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA., Cetin Z; Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA., Frau C; Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA., Vernetti L; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, USA.; University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA., Amler AK; Cellbricks GmbH, Gustav-Meyer-Allee 25, 13355 Berlin, Germany., Thomas A; Cellbricks GmbH, Gustav-Meyer-Allee 25, 13355 Berlin, Germany., Lam T; Cellbricks GmbH, Gustav-Meyer-Allee 25, 13355 Berlin, Germany., Kloke L; Cellbricks GmbH, Gustav-Meyer-Allee 25, 13355 Berlin, Germany., Takeishi K; Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan., Taylor DL; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, USA.; University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA., Fox IJ; Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Surgery, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA, USA.; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA., Soto-Gutierrez A; Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, USA.; University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, USA.; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Jazyk:	angličtina
Zdroj:	IScience [iScience] 2022 Nov 04; Vol. 25 (12), pp. 105503. Date of Electronic Publication: 2022 Nov 04 (Print Publication: 2022).
DOI:	10.1016/j.isci.2022.105503
Abstrakt:	Advances in cellular engineering, as well as gene, and cell therapy, may be used to produce human tissues with programmable genetically enhanced functions designed to model and/or treat specific diseases. Fabrication of synthetic human liver tissue with these programmable functions has not been described. By generating human iPSCs with target gene expression controlled by a guide RNA-directed CRISPR-Cas9 synergistic-activation-mediator, we produced synthetic human liver tissues with programmable functions. Such iPSCs were guide-RNA-treated to enhance expression of the clinically relevant CYP3A4 and UGT1A1 genes, and after hepatocyte-directed differentiation, cells demonstrated enhanced functions compared to those found in primary human hepatocytes. We then generated human liver tissue with these synthetic human iPSC-derived hepatocytes (iHeps) and other non-parenchymal cells demonstrating advanced programmable functions. Fabrication of synthetic human liver tissue with modifiable functional genetic programs may be a useful tool for drug discovery, investigating biology, and potentially creating bioengineered organs with specialized functions. Competing Interests: A.C.-H., K.T., I.J.F., and A.S.-G. are inventors on a provisional international patent application that describes hepatic differentiation of human pluripotent stem cells and liver repopulation (PCT/US2018/018032) and a provisional international patent application that describes the use of human-induced pluripotent stem cells for highly genetic engineering (PCT/US2017/044719). A.S.-G., J.G.-L., A.C.-H., and I.J.F. are co-founders and have a financial interest in Von Baer Wolff, Inc. a company focused on biofabrication of autologous human hepatocytes from stem cells technology. I.J.F. and A.S.-G. are co-founders and have a financial interest in Pittsburgh ReLiver Inc, a company focused on programming liver failure and their interests are managed by the Conflict-of-Interest Office at the University of Pittsburgh in accordance with their policies. (© 2022 The Authors.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu