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Glucocorticoid signaling enhances expression of glucose-sensing molecules in immature pancreatic beta-like cells derived from murine embryonic stem cells in vitro

Ghazalli, Nadiah and Wu, Xiaoxing and Walker, Stephanie and Trieu, Nancy and Hsin, Li-Yu and Choe, Justin and Chen, Chialin and Hsu, Jasper and LeBon, Jeanne and Kozlowski, Mark T. and Rawson, Jeffrey and Tirrell, David A. and Yip, M. L. Richard and Ku, Hsun Teresa (2018) Glucocorticoid signaling enhances expression of glucose-sensing molecules in immature pancreatic beta-like cells derived from murine embryonic stem cells in vitro. Stem Cells and Development, 27 (13). pp. 898-909. ISSN 1547-3287. PMCID PMC6029647. doi:10.1089/scd.2017.0160.

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Pluripotent stem cells may serve as an alternative source of beta-like cells for replacement therapy of type 1 diabetes; however, the beta-like cells generated in many differentiation protocols are immature. The maturation of endogenous beta cells involves an increase in insulin expression starting in late gestation and a gradual acquisition of the abilities to sense glucose and secrete insulin by week 2 after birth in mice; however, what molecules regulate these maturation processes are incompletely known. Here, we aim to identify small molecules that affect immature beta cells. A cell-based assay, employing pancreatic beta-like cells derived from murine embryonic stem (ES) cells harboring a transgene containing an Insulin 1-promoter driven enhanced green fluorescent protein reporter, was used to screen a compound library (NIH Clinical Collection-003). Cortisone, a glucocorticoid, was among five positive hit compounds. Quantitative RT-PCR analysis revealed that glucocorticoids enhance the gene expression of not only insulin 1 but also glucose transporter-2 (Glut2; Slc2a2) and glucokinase (Gck), two molecules important for glucose sensing. Mifepristone, a pharmacological inhibitor of glucocorticoid receptor (GR) signaling, reduced the effects of glucocorticoids on Glut2 and Gck expression. The effects of glucocorticoids on ES-derived cells were further validated in immature primary islets. Isolated islets from 1-week-old mice had an increased Glut2 and Gck expression in response to a 4-day treatment of exogenous hydrocortisone in vitro. Gene deletion of GR in beta cells using rat insulin 2 promoter-driven Cre crossed with GRflox/flox mice resulted in a reduced gene expression of Glut2, but not Gck, and an abrogation of insulin secretion when islets were incubated in 0.5 mM D-glucose and stimulated by 17 mM D-glucose in vitro. These results demonstrate that glucocorticoids positively regulate glucose sensors in immature murine beta-like cells.

Item Type:Article
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Tirrell, David A.0000-0003-3175-4596
Additional Information:© 2018 Mary Ann Liebert, Inc. publishers. Received for publication August 1, 2017; Accepted after revision April 30, 2018; Prepublished on Liebert Instant Online May 2, 2018. The authors thank Donna Isbell and Kelley Carpenter from the Animal Research Center of City of Hope for assistance in breeding the GR β-cell KO mice. The authors also thank Dr. Manami Hara for providing MIP-EGFP ES cells. This work was supported, in part, by the National Institutes of Health (R01DK081587 and R01DK099734 to H.T.K. and P30CA33572 to City of Hope). Support from the Oxnard Foundation, Ella Fitzgerald Foundation and the Wanek Family Project of Type 1 Diabetes to H.T.K. is also gratefully acknowledged. N.G. was supported by a predoctoral fellowship as part of an institutional grant to City of Hope from the California Institute for Regenerative Medicine (CIRM). Work at California Institute of Technology was supported by the Department of Defense (DoD) through the National Defense Science & Engineering Graduate Fellowship (NDSEG) Program to M.T.K. and by National Science Foundation grant DMR 1506483 to D.A.T. The sponsor did not participate in the study design, collection, analysis, and interpretation of data. No competing financial interests exist.
Funding AgencyGrant Number
Oxnard FoundationUNSPECIFIED
Ella Fitzgerald FoundationUNSPECIFIED
Wanek Family Project of Type 1 DiabetesUNSPECIFIED
Department of DefenseUNSPECIFIED
National Defense Science and Engineering Graduate (NDSEG) FellowshipUNSPECIFIED
Subject Keywords:small molecule screening, immature beta cells, murine embryonic stem cells, glucose sensors, postnatal young islets
Issue or Number:13
PubMed Central ID:PMC6029647
Record Number:CaltechAUTHORS:20180507-075120790
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Official Citation:Glucocorticoid Signaling Enhances Expression of Glucose-Sensing Molecules in Immature Pancreatic Beta-Like Cells Derived from Murine Embryonic Stem Cells In Vitro. Ghazalli Nadiah, Wu Xiaoxing, Walker Stephanie, Trieu Nancy, Hsin Li-Yu, Choe Justin, Chen Chialin, Hsu Jasper, LeBon Jeanne, Kozlowski Mark T., Rawson Jeffrey, Tirrell David A., Yip M.L. Richard, and Ku Hsun Teresa. Stem Cells and Development 2018 27:13, 898-909
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:86231
Deposited By: Tony Diaz
Deposited On:07 May 2018 15:05
Last Modified:15 Nov 2021 20:36

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