Understanding pancreatic development is instrumental to diabetes research and β-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.

Keywords:
Pancreas, Glucocorticoid, GR, β-Cell, Multipotent, Bipotent, Endocrine, Progenitor, FRZB, LINC02381
Subjects:
Cell fate control and differentiation, Gene regulation, Signalling

Author contributions

Conceptualization: L.V., S.A.R.-S.; Data curation: A.C.H., D.M.; Formal analysis: S.A.T., L.B., A.C.H., D.M., S.A.R.-S.; Funding acquisition: L.V., S.A.R.-S.; Investigation: S.A.T., L.B., A.C.H., L.V., S.A.R.-S.; Methodology: S.A.T., L.B., A.C.H., D.M., J.G.-B., C.G., F.L., J.I.B., A.R., M.C.; Project administration: S.A.R.-S.; Resources: A.P., L.V., S.A.R.-S.; Supervision: S.A.R.-S.; Validation: S.A.T., L.B., D.F., I.T., M.C.; Visualization: L.B., A.C.H.; Writing – original draft: S.A.T., L.B., A.P., L.V., S.A.R.-S.; Writing – review & editing: S.A.R.-S.

Funding

S.A.R.-S. and A.P. are career investigators from the Consejo Nacional de Investigaciones Científicas y Técnicas of Argentina (CONICET). This work was supported by the CONICET/Royal Society International Exchanges Cost Share 2018 (IEC\R2\181023 to L.V. and S.A.R.-S.). The S.A.R.-S. laboratory is funded by grants from Agencia Nacional de Promoción Científica y Tecnológica of Argentina (PICT-2015 3605, PICT-2019 00374) and the Universidad de Buenos Aires (UBACYT 20020170200156BA). The L.V. laboratory is funded by a European Research Council advanced FunChol grant, a core support grant from the Berlin Institute of Health and the Max Planck Society (Max-Planck-Gesellschaft). S.A.T., L.B., A.C.H. A.R. are supported by PhD fellowships from CONICET. J.I.B. was supported by a postdoctoral fellowship from Agencia Nacional de Promoción Científica y Tecnológica of Argentina. I.T. is funded by an EMBO long-term fellowship and D.F. by an ELES studentship.

Data and resource availability

All raw and processed sequencing data generated in this study have been submitted to the NCBI's Gene Expression Omnibus under accession number GSE237280.

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