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.

In silico discovery of small molecules for efficient stem cell differentiation into definitive endoderm

“…Overall, SCENIC results were in agreement with those of the bulk RNA-seq analysis. Consistent with previous reports, SCENIC identified endoderm-related markers, including LHX1 and KLF6/8 (Chu et al 2016), OTX2 andFOXA2 (Fu et al 2011), SOX17 (Qu et al 2008), EOMES and ETS1/2 (Mohammadnia et al 2016), FOXQ1 (Shiraki, Ogaki, andKume 2014), andSIX3 (Jing Wen et al 2017). It also revealed potentially new markers such as RREB1, CUX1, IRF9, DDIT3, TFAP2C, PBX3, JUN, and JUND (Fig.…”

METTL1-mediated m7G methylation maintains pluripotency in human stem cells and limits mesoderm differentiation and vascular development

“…RNA-seq analysis in METTL1-KD hiPSCs revealed an apparent downregulation of genes involved in maintaining stem cell self-renewal and pluripotency, including BMP4, FGF2, and WNT2. Simultaneously, various pathways associated with stem cell regulation were significantly downregulated [ 32 , 33 ]. P53 signaling pathway has been considered to play an active role in promoting cell apoptosis and also plays a critical role in inhibiting the cell cycle of ESCs [ 34 ].…”

Networks Models of Actin Dynamics during Spermatozoa Postejaculatory Life: A Comparison among Human-Made and Text Mining-Based Models

“…We paid our attention to text mining because it represents a new, important, and fascinating resource for information retrieval [4] and for constructing interaction network from biomedical texts [5]. Recently, this approach has been adopted to explore the biology of different phenomena, such as the prostate cancer protein interaction network, by using a reinforcement learning-based algorithm [5], or in studying other types of tumours [6–9] and physiological [10–12] and pathological events [13–15]. Here, in detail, we realize a model, starting from the analysis of published literature on this topic and we compared it with models realized by two different text mining tools, able to produce networks: Agilent Literature Search and PESCADOR.…”