Endocrine Pancreas Development and Regeneration: Noncanonical Ideas From Neural Stem Cell Biology

Abstract

Loss of insulin-producing pancreatic islet β-cells is a hallmark of type 1 diabetes. Several experimental paradigms demonstrate that these cells can, in principle, be regenerated from multiple endogenous sources using signaling pathways that are also used during pancreas development. A thorough understanding of these pathways will provide improved opportunities for therapeutic intervention. It is now appreciated that signaling pathways should not be seen as “on” or “off” but that the degree of activity may result in wildly different cellular outcomes. In addition to the degree of operation of a signaling pathway, noncanonical branches also play important roles. Thus, a pathway, once considered as “off” or “low” may actually be highly operational but may be using noncanonical branches. Such branches are only now revealing themselves as new tools to assay them are being generated. A formidable source of noncanonical signal transduction concepts is neural stem cells because these cells appear to have acquired unusual signaling interpretations to allow them to maintain their unique dual properties (self-renewal and multipotency). We discuss how such findings from the neural field can provide a blueprint for the identification of new molecular mechanisms regulating pancreatic biology, with a focus on Notch, Hes/Hey, and hedgehog pathways.

An Activating STAT3 Mutation Causes Neonatal Diabetes through Premature Induction of Pancreatic Differentiation

“…However, we did not detect any significant changes in the expression of NEUROG3 upstream regulators or in the genes associated with Notch signaling. A non-canonical Notch signaling axis involving phosphatidylinositol 3-kinase (PI3K)-Akt-mTOR, STAT3-Ser phosphorylation, and HES3 has also been suggested to control NEUROG3 activation (Masjkur et al, 2016), but we could not detect any changes in HES3 transcriptional levels in our experiments (data not shown). Thus, the premature upregulation of NEUROG3 caused by the STAT3 mutation does not seem to be mediated by perturbations in the known developmental mechanisms controlling NEUROG3.…”

Interleukin‐17/interleukin‐17 receptor axis elicits intestinal neutrophil migration, restrains gut dysbiosis and lipopolysaccharide translocation in high‐fat diet‐induced metabolic syndrome model

“…In addition, immunohistochemistry was performed to assess insulin expression in these cells. There are reports in the literature showing that in the initial phase of MetS a process of proliferation and/or regeneration of insulin‐producing β cells occurs as a compensatory mechanism to normalize high blood glucose levels . Indeed, we noted a hyperplasia of pancreatic islets in both WT and IL‐17RA −/− mice fed the HFD compared with mice on the CD (Fig.…”

Controlling distinct signaling states in cultured cancer cells provides a new platform for drug discovery

“…Oligodendrocyte progenitors also express HES3 in the adult mammalian brain (38). Beyond the brain, HES3+ cells are also found in the pancreas (a significant percentage of b-cells express HES3) (34,43) and the adrenal gland [HES3 expression has been reported in adrenomedullary chromaffin progenitors of the medulla and the zona glomerulosa of the adrenal cortex, where cortical stem cells are thought to reside (35,44)].…”