Glucocorticoid-receptor molecular mechanisms controlling pancreas development and endocrine cell specification

GARCÍA-BERNARDO, JOSÉ; VALLIER, LUDOVIC; CHHATRIWALA, MARIYA; RODRÍGUEZ SEGUÍ, S.A.; TRABA, S.A.; PECCI, ADALI

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Simposio; Fourth South American Symposium in Signal Transduction and Molecular Medicine (SISTAM); 2018

Thein vitroproduction of functional β cells for transplantation in type 1diabetic patients is a long-standing goal to achieve, which wouldallow the suppression of insulin administration. Currentdifferentiation protocols to derive β cells from human pluripotentstem cells (hPSCs) artificially mimic the cell signaling events thatoccur during fetal development, and involve manipulation of signalingpathways that are known to play key and stage-specific roles duringpancreas growth and differentiation. Thus, gaining insights into themechanisms by which novel pathways control this process mightsignificantly impact this field of research. Previous studies haveshown that the glucocorticoid receptor (GR) signaling pathway playsan important role in the generation of an appropriate number of βcells to accomplish an accurate glycemic control in adults, althoughthe underlying molecular mechanisms still remain largely unexplored.We have previously reported the construction of genomic cisregulatory maps in human pancreatic islets and in the human embryonicpancreas based on ChIP-seq and RNA-seq experiments. In the lattercase we used human pancreatic buds that were dissected from 6-7 wpcembryos and cells from a matched differentiation stage that were invitro derived from hPSCs.Our analyses led to the discovery that TEAD and YAP are important gene expression regulators that in the embryonic pancreas are in charge of maintaining the pancreatic multipotent progenitor cell (MPC)phenotype. Further analysis of this resource shows that a subset ofthe genes that are highly expressed in MPCs could be downregulated upon activation of the GR pathway. Using invitro mouse and human models of pancreas development, our current efforts are focused in understanding how glucocorticoids affect the gene expression program in pancreatic progenitor cells at different developmental stages.p { margin-bottom: 0.1in; direction: ltr; line-height: 115%; text-align: left; }a:link { color: rgb(5, 99, 193); }