|Yoshiya Kawaguchi M.D., Ph.D.
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Since the advent of ES cells and iPS cells, many researchers have attempted to induce pancreatic endocrine cells exploring a future regenerative therapy for diabetes, but we still have not succeeded in creating functional pancreatic islets. In our laboratory, we would like to tackle this issue using the concept of "learning from phenomena that actually occur in the living body", that is, not only analyzing the normal developmental pathway and adult organ maintenance machinery but also investigating the abnormal phenomena such as congenital abnormalities and diseases including ectopic pancreas formation. Evolutional aspects of pancreas development in vertebrates would also provide insights for this issue.
Using transgenic mice experiments, we have previously clarified the following.
(1) A transcription factor ptf1a functions as the pancreas determiner in the cell fate choice of undifferentiated endodermal epithelia towards duodenal, bile duct and pancreatic cells.
(2) In the process above, differentiation into the pancreas is decided through the dosage control of ptf1a expression.
(3) Inactivation of Hes1, a main effecter in Notch signaling, induces ectopic ptf1a expression and pancreas formation in the restricted portion within the endogenous Hes1-expressing domain. Hes1 functions as a negative regulator of ptf1a, and only the portion at which the ptf1a expression level reaches a certain threshold, which is ultimately determined by the balance with an unknown ptf1a inducing signal, will thus become the pancreas.
(4) Embryonic Sox9 positive cells in the pancreas can differentiate into all types pancreatic cells but their multipotency diminishes around one week of age when endocrine cell clusters detach from the duct structure and form islet structure. Adult Sox9 positive cells function as exocrine progenitors but cannot differentiate into endocrine lineages. In order to succeed in meeting the above described challenge, we believe that it is important to reproduce a comprehensive picture of the mechanism in pancreas development by cumulatively performing the task of confirming new findings that are obtained in the course of iPS cell-based inducing experiments with experiments on pancreas development.