title: Signaling and Gene Regulatory Networks Governing Definitive Endoderm Derivation From Pluripotent Stem Cells.
abstract: The generation of definitive endoderm (DE) from pluripotent stem cells (PSCs) is a fundamental stage in the formation of highly organized visceral organs, such as the liver and pancreas. Currently, there is a need for a comprehensive study that illustrates the involvement of different signaling pathways and their interactions in the derivation of DE cells from PSCs. This study aimed to identify signaling pathways that have the greatest influence on DE formation using analyses of transcriptional profiles, protein-protein interactions, protein-DNA interactions, and protein localization data. Using this approach, signaling networks involved in DE formation were constructed using systems biology and data mining tools, and the validity of the predicted networks was confirmed experimentally by measuring the mRNA levels of hub genes in several PSCs-derived DE cell lines. Based on our analyses, seven signaling pathways, including the BMP, ERK1-ERK2, FGF, TGF-beta, MAPK, Wnt, and PIP signaling pathways and their interactions, were found to play a role in the derivation of DE cells from PSCs. Lastly, the core gene regulatory network governing this differentiation process was constructed. The results of this study could improve our understanding surrounding the efficient generation of DE cells for the regeneration of visceral organs. J. Cell. Physiol. 231: 1994-2006, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran.
authors.forename: Abdulshakour
authors.initials: A
authors.lastname: Mohammadnia
authors.affiliation: Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran.|Ludmer Centre for Neuroinformatics and Mental Health, McGill University, Montréal, Quebec, Canada.|Douglas Mental Health University Institute, McGill University, Montréal, Quebec, Canada.
authors.forename: Moein
authors.initials: M
authors.lastname: Yaqubi
authors.affiliation: Department of Biotechnology, Razi Vaccine and Serum Research Institute, Karaj, Iran.|Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Farzaneh
authors.initials: F
authors.lastname: Pourasgari
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Neely
authors.affiliation: Department of Biology, School of Science, Razi University, Kermanshah, Iran.|Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.
authors.forename: Hossein
authors.initials: H
authors.lastname: Fallahi
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.|Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Massumi
mesh_terms: D028341:Activins / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D004707:Endoderm / Q000166:cytology*; D053263:Gene Regulatory Networks; D000066449:Human Embryonic Stem Cells / Q000166:cytology; D006801:Humans; D010179:Pancreas / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D016212:Transforming Growth Factor beta; D028341:Activins