A principle obstacle in regenerative medicine is the lack of renewable sources of human cells for the transplant-based treatment of liver diseases and diabetes. Human biliary tree stem/progenitor cells (hBTSCs) have multipotential differentiation capability, comprising hepatocyte, cholangiocyte and pancreatic islet fates. Recently, we demonstrated that in human duodenum, submucosal glands (SG) contain cells with endodermal features and capable to differentiate in vitro and in vivo to liver and pancreatic islet fates. The translation of these discoveries to a next application requires pre-clinical studies. Adipose-derived stem cells (ASCs) are one of the most widely studied and used source in regenerative medicine, since they are endowed with favorable properties and release paracrine factors know to act positively in the process of tissue regeneration. The main aim of this project is to investigate the role of hBTSCs and duodenal SGs in rescuing experimental murine models of liver injuries and type I diabetes, and to increase the proliferation and the effects of these endodermal-derived cells through the use of ASCs. The project will be subdivided in working packages (WPs) with specific objectives. WP#1 will optimize long term in vitro expansion and organoid formation of hBTSCs and duodenal SGs through co-culturing with ASCs. WP#2 will compare the effects of hBTSCs and duodenal SGs differentiated in hepatocytes in engrafting into the liver and rescuing experimental models of liver injuries in SCID mice. WP#3 will compare the effects of hBTSCs and duodenal SGs differentiated in ß cells transplanted in the fat pad in rescuing a stretozotocin-induced model of diabetes in SCID mice. WP#4 will assess the potential application of both cellular sources to regenerative medicine combining the favorable features and functions of the endodermal stem cell populations with the beneficial roles played by ASCs and their secreted proteins in an in vitro and in an vivo modelling.
