@article{af07967d44014e33851ed6c0a487669f,
title = "Robust, Long-Term Culture of Endoderm-Derived Hepatic Organoids for Disease Modeling",
abstract = "Organoid technologies have become a powerful emerging tool to model liver diseases, for drug screening, and for personalized treatments. These applications are, however, limited in their capacity to generate functional hepatocytes in a reproducible and efficient manner. Here, we generated and characterized the hepatic organoid (eHEPO) culture system using human induced pluripotent stem cell (iPSC)-derived EpCAM-positive endodermal cells as an intermediate. eHEPOs can be produced within 2 weeks and expanded long term (>16 months) without any loss of differentiation capacity to mature hepatocytes. Starting from patient-specific iPSCs, we modeled citrullinemia type 1, a urea cycle disorder caused by mutations in the argininosuccinate synthetase (ASS1) enzyme. The disease-related ammonia accumulation phenotype in eHEPOs could be reversed by the overexpression of the wild-type ASS1 gene, which also indicated that this model is amenable to genetic manipulation. Thus, eHEPOs are excellent unlimited cell sources to generate functional hepatic organoids in a fast and efficient manner.",
keywords = "3D organoid, citrullinemia, disease modelling, EpCAM, hepatocyte, hepatocyte differentiation, iPSC, liver",
author = "Soheil Akbari and Sevin{\c c}, \{G{\"u}lben G{\"u}rhan\} and Nevin Ersoy and Onur Basak and Kubra Kaplan and Kenan Sevin{\c c} and Erkin Ozel and Berke Sengun and Eray Enustun and Burcu Ozcimen and Alper Bagriyanik and Nur Arslan and {\"O}nder, \{Tamer Tevfik\} and Esra Erdal",
note = "Funding Information: We would like to thank to Prof. Dr. Hans Clevers (Hubrecht Institute/KNAW, Utrecht, the Netherlands) for hosting S.A. in the Hubrecht Institute (Utrecht, the Netherlands) and for the kind gift of L-Wnt3a and Noggin cell lines. We are also immensely grateful to the members of Clevers Lab for sharing their experience about organoid culture. Finally, we would gratefully like to thank Melek Ucuncu and Muge Ozkan for their help in interpreting the imaging and flow-cytometry data, respectively. This research was supported by TUBİTAK (The Scientific and Technological Research Council of Turkey ) via projects SBAG-115S465 and SBAG-213S182 and by an EMBO installation grant no. 2543 (T.T.O.). K.S. was supported by a TUBITAK BIDEB Scholarship. The authors gratefully acknowledge use of the services and facilities of the Ko{\c c} University Research Center for Translational Medicine (KUTTAM) and of the Izmir Biomedicine and Genome Center, both funded by the Republic of Turkey Ministry of Development . The content is solely the responsibility of the authors and does not necessarily represent the official views of the Ministry of Development. Funding Information: We would like to thank to Prof. Dr. Hans Clevers (Hubrecht Institute/KNAW, Utrecht, the Netherlands) for hosting S.A. in the Hubrecht Institute (Utrecht, the Netherlands) and for the kind gift of L-Wnt3a and Noggin cell lines. We are also immensely grateful to the members of Clevers Lab for sharing their experience about organoid culture. Finally, we would gratefully like to thank Melek Ucuncu and Muge Ozkan for their help in interpreting the imaging and flow-cytometry data, respectively. This research was supported by TUB?TAK (The Scientific and Technological Research Council of Turkey) via projects SBAG-115S465 and SBAG-213S182 and by an EMBO installation grant no. 2543 (T.T.O.). K.S. was supported by a TUBITAK BIDEB Scholarship. The authors gratefully acknowledge use of the services and facilities of the Ko? University Research Center for Translational Medicine (KUTTAM) and of the Izmir Biomedicine and Genome Center, both funded by the Republic of Turkey Ministry of Development. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Ministry of Development. Publisher Copyright: {\textcopyright} 2019 The Authors",
year = "2019",
month = oct,
day = "8",
doi = "10.1016/j.stemcr.2019.08.007",
language = "English",
volume = "13",
pages = "627--641",
journal = "Stem Cell Reports",
issn = "2213-6711",
publisher = "Cell Press",
number = "4",
}