Exploiting vascular signals to improve the functional maturation of iPSC-derived beta-like cells

Diabetes mellitus is a pandemic disease that remains hitherto without
a cure for most patients. Transplantation of cadaveric human islets
provides convincing evidence that cell replacement can truly cure
diabetes. Unfortunately, donor scarcity, impaired graft
revascularization and the need for lifelong immunosuppression
prevent widespread application of islet cell transplantation. Beta-like
cells derived from induced pluripotent stem cells (iPSC-ß) are a
promising alternative cell source for transplantation as they
circumvent donor cell scarcity and enable molecular strategies to
overcome immune rejection. However, in vitro-generated iPSC-ß 
remain functionally immature and require transplantation to more
closely resemble adult beta cells. Although Vascular Endothelial
Growth Factor-A (VEGF-A) and endothelial cell signalling are key to
pancreatic endocrinogenesis, adult beta cell function, and primary
islet cell engraftment, the role of VEGF-A and endothelial cells in
iPSC-ß maturation is currently unknown. The objective of this
research project is to investigate the contribution of vascular-derived
signals to iPSC-ß cell maturation and function in vitro and at different
islet engraftment sites. To this extent, we will use innovative genetic,
molecular and cellular methods in gain and loss-of-function
experiments. This project will yield fundamental new insights that will
contribute to the cardinal preclinical aim of improving the outcome of
iPSC-ß transplantation