Role of the Glucagon-like Peptide-1 Receptor Agonist in Maintaining Pluripotency in Human Embryonic Stem Cells



Methichit Chayosumrit*, 1, Anandwardhan A. Hardikar2, Bernard E. Tuch , Kuldip S. Sidhu1
Stem Cell Laboratory, School of Psychiatry, Faculty of Medicine, University of New South Wales, NSW, Australia.
2Diabetes and Pancreas Biology Section, The O'Brien Institute, St Vincent's Hospital, The University of Melbourne, Melbourne, VIC, Australia


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Chayosumrit et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Address correspondence to this author at the Stem Cell Laboratory, School of Psychiatry, Faculty of Medicine, University of New South Wales, NSW, Australia. methichit@gmail.com


Abstract

Previous studies have demonstrated that glucagon-like peptide-1 (GLP-1) stimulates β-cell formation and insulin secretion. Currently, there has been no report in understanding the effect of GLP-1 / its agonist exendin-4 in differentiation of human embryonic stem cells (hESCs) to definitive endodermal (DE). We hypothesized that exendin-4 signaling in hESCs via GLP-1 receptor (GLP-1R) may have potential role in DE differentiation. The effect of Ex-4 on pluripotent hESCs and the combined effect of Ex-4 and activin A-treated hESC-derived DE were examined. Analysis by quantitative real-time PCR (qPCR) demonstrates that Ex-4 alone was not sufficient to enhance DE formation in hESCs. On the other hand, a combinatorial treatment with activin A and Ex-4 resulted in significant decrease in expression levels of DE markers. The miRNA expression profiles between activin A-treated hESCs and activin A/Ex-4-treated hESCs after 5 days of treatment demonstrated similar expression levels of endoderm and pancreas-associated miRNAs. However, it was shown that the levels of pluripotency-associated miRNAs, miR-302a* and miR302c*, were upregulated in the presence of Ex-4. Furthermore, it was observed that exposure to bFGF and Ex-4 in apoptosis-inducing medium resulted in downregulation of CASP3 and p53. Taken together, these data revealed the possibility of Ex-4 in maintaining pluripotency and inhibiting apoptosis. The knowledge of GLP-1 signaling pathways could be useful for understanding the mechanism of GLP-1R-ligand interactions and their relevance to hESC development.

Keywords: Human embryonic stem cells , glucagon-like peptide-1, differentiation, definitive endoderm.