Our preliminary data shows that the major type of cells in the normal pancreas-the exocrine cells-is capable of reverting to a phenotype resembling that of the pancreatic precursor ells found normally during the development of the pancreas. This process occurs during surgical induction of pancreatic regeneration in rodents, and is characterized by dedifferentiation of mature exocrine cells into an epithelial precursor type expressing the transcription factors Pdx1 and Hes1. Both of these genes are normally markers of the undifferentiated embryonic pancreatic cells, which are capable of further developing into all cell types of the mature organ. Furthermore, the expression of Hes1 strongly suggests that the Notch-signaling mechanism is reactivated by these cells. Our recent data provides evidence that Notch-signaling is of crucial importance in the maintenance of the pancreatic precursor cell state during normal development. The fact that most cells of the pancreas, the exocrine cell type, is capable of reverting to a stem-cell line character is noteworthy, as these cells than may be targets for conversion into endocrine cells. Our proposal is to understand the regenerative process by further analysis of Notch-signaling system through the time points of pancreatic regeneration, and to identify the signaling mechanism that induces this transition. Although our data shows that endocrine development is not normally occurring at a significant rate during pancreatic regeneration, we hypothesize that the reinstatement of the precursor cell state will allow for this, if a proper inducing signal is provided. For that reason, we will experimentally seek to modulate endocrine development from these cells by instating an endocrine program de-novo. This will be done by using inducible recombination of the pro-endocrine gene ngn3, which is targeted to the pancreatic precursor cells. Using this system, we will evaluate the capability of ngn3 in promoting the endocrine fate choice in the adult pancreas. Successful results may be of extreme importance for future islet-replacement therapies for diabetics.
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