Stimulation of beta cell neogenesis by EGF and CNTF

Type l-diabetes is characterized by an absolute shortage of beta cells in the pancreas. Restoration of the normal beta cell mass might be obtained by beta cell regeneration from progenitors. This regeneration strategy requires that the autoimmune destruction of beta cells can be controlled. Recently, it was shown that beta cell progenitors, expressing the embryonic transcription factor Ngn3, are activated in the adult mouse pancreas when tissue damage is induced by duct ligation. Our aim is to activate these progenitors in a way better suited for therapeutical application (without inducing extensive tissue damage); via treatment with growth factors and cytokines. Our group fouod that the combination of LIF/CNTF and EGF can induce Ngn3-expression and beta cell neogenesis in in vitro cultures of adult rat pancreas. Therefore, we are currently investigating whether these factors can activate Ngn3-progenitors in vivo. This project aims at expanding our in vitro data from rat pancreas to mouse and human pancreas. We also want to elucidate the origin of the Ngn3-progenitors and induce progenitor activation by stimulating downstream signaling pathways of LIF and EGF. Furthermore, we want to study the role of LIP and EGF in physiological beta cell regeneration (within the duct ligation model).