UCLA

An important aim of Type I diabetes therapeutic strategies is the replenishment of functional beta cells. Directing the efficient differentiation of stem cell sources in vitro into functional insulin secreting beta cells is the preferred approach, however, existing experimental protocols have not been able to successfully yield functionally responsive insulin positive cells. One obstacle in this approach can be attributed to gaps in the understanding of mechanisms that regulate pancreatic beta cell development in vivo. This research work seeks to better understand the mechanisms by which important genetic and epigenetic regulators govern pancreatic cell fate specification and maintenance.

Our data reveals that microRNAs (miRNAs) - post-transcriptional regulators of gene expression - play an important role in the functional maintenance and survival of newly specified pancreatic beta cells. In the absence of the miRNA-processing enzyme Dicer1, newly specified beta cells lose insulin expression and acquire a neuronal transcriptional profile. The deregulation of neuronal genes is associated with a loss of binding of the neuronal transcriptional repressor REST to its neuronal target genes. This suggests that miRNAs play an important role in modulating critical regulators of cell fate during pancreatic islet cell development.

Interestingly, an investigation into a role for REST during early pancreatic development revealed that activation of REST target genes in pancreatic progenitors resulted in the epithelium adopting a progenitor and duct-like state with defects in endocrine and acinar cell specification. This data argues for a previously unknown role for REST in modulating pancreatic organogenesis.

In addition to discovering novel transcriptional regulators of pancreatic development, our data provides insights into a critical role for a DNA methyltransferase - DNMT1 - in coordinating pancreatic organogenesis. Abrogation of DNMT1 expression in pancreatic progenitors resulted in p53-dependant apoptosis of the progenitors that was subsequently rescued upon introduction of p53 haploinsufficiency to the DNMT1 deficient progenitors.

This body of work adds to the overall understanding of normal embryonic pancreas development and may guide the creation of efficient beta cell differentiation protocols allowing for in vitro differentiated beta cells to possibly become an important source for replenishing beta cells in diabetic patients