Glucocorticoid receptor molecular mechanisms controlling pancreas development and endocrine cell specification

TRABA, S.A.; CHHATRIWALA, MARIYA; RODRÍGUEZ SEGUÍ, S.A.; BURGOS, I.; PECCI, A.; GARCIA-BERNARDO, J.; VALLIER, L.

Reunión virtual

Congreso; Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2020

Sociedad Argentina de Investigación Clínica

The invitro production of functional βcells for transplantation in type 1 diabetic patients is along-standing goal to achieve. Current differentiation protocols toderive β cells from human pluripotent stemcells mimic the cell signaling events that occur during fetaldevelopment, and involve manipulation of signaling pathways that areknown to play key and stage-specific roles during pancreas growth anddifferentiation. Thus, gaining insights into the mechanisms by whichnovel pathways control this process might significantly impact thisfield of research. Previous studies have shown that theglucocorticoid receptor (GR) signaling pathway plays an importantrole in the generation of an appropriate number of βcells in adults, although the underlying molecular mechanisms stillremain largely unexplored. We have previously reported theconstruction of genomic cisregulatory maps in human pancreatic islets and in the human embryonicpancreas based on ChIP-seq and RNA-seq experiments.Our analyses led to the discoverythat TEAD and YAP are important gene regulators in the embryonicpancreas, in charge of maintaining the pancreatic multipotentprogenitor cell phenotype. Further analysis shows that a subset ofthe genes that are highly expressed in MPCscould be downregulated upon activation of the GR pathway. We usedmouse pancreatic explants to assess the transcriptomic effects ofGCtreatment during early development, finding that endocrinefate-related genes were downregulated. We also profiled bysingle-cell RNA-seq the transcriptional changes induced by GCtreatment of MPCs and BP/EPs derivedin vitro from hiPS cells. Analysis of these data suggested newplayers modulating the MPC and BP/EP cell response to GC in humans.Our current work is focused in validating such results in the murinemodel. Our preliminary results suggest that, despite severalsimilarities between mouse and human pancreatic developmentalprograms have been reported, there may be substantial diferences inthe transcriptional reponse to the GC effects. p { margin-bottom: 0.1in; direction: ltr; line-height: 115%; text-align: left; orphans: 2; widows: 2 }