Endogenous Glucocorticoid Receptor Activation Modulates Early-Stage Cell Differentiation in Pancreatic Progenitors of Mice and Humans
Understanding pancreatic development is instrumental to diabetes research and ß-cell replacement therapies. Here, we investigate glucocorticoid receptor (GR) signaling during early pancreas development in mice and humans. Previous reports suggest that glucocorticoids do not play a significant role in mouse pancreas development before the second transition. In this study, we demonstrate that, under physiological conditions, the GR is selectively active in mouse pro-acinar and early endocrine cells from embryonic day 11.5, silenced in bipotent progenitors, and reactivated during endocrine commitment. In mouse pancreatic explants, ectopic GR activation globally promotes acinar fate. Surprisingly, GR activation in human in vitro-derived multipotent pancreatic progenitors steers lineage commitment toward a bipotent/endocrine trajectory and upregulates genes for which expression profiles resemble those of SOX9 and HES1 during human embryonic pancreatic bipotential and endocrine progenitor fate choice. Our combined epigenomic and single-cell transcriptomic analyses suggest that these newly identified marker genes may play important roles in human pancreas development. Taken together, our findings position the GR pathway as an endogenous developmental modulator of early-stage pancreatic progenitor cell differentiation and provide insights into the underlying transcriptional mechanisms involved. Overall design: Pancreatic differentiation was induced in FSPS13.B human induced pluiripotent stem cells. To generate the treatments on Day 13 (multipotent pancreatic progenitor stage) and Day 16 (bipotent/endocrine progenitor stage) cells, dexamethasone (Dex, 100nM) or the EtOH vehicle (Ctrl) were added to the corresponding culture medium composition 24 h before cell collection. Thus, to generate Day 13 treated and untreated cells, Dex or EtOH was added on day 12 to the days 9-13 media composition. To generate Day 16 treated and untreated cells, Dex or EtOH was added on day 15 to the days 14-16 media composition.