PhD candidate Mitchell Maloy from Parashurama research group is leading a project aiming to engineer a human pluripotent stem cells-derived pancreatic progenitor for Islet cell development.
Type 1 diabetes mellitus is characterized by the autoimmune destruction of insulin-producing b-cells within the pancreatic islets, the endocrine portion of the pancreas. Current treatment methods rely on the administration of exogenous insulin, which only mitigates the disease. Human pluripotent stem cells (hPSCs) are an intriguing option to replace the b-cells in patients. Approaches for b-cell replacement therapies follow either hPSC differentiation in vitro to mature, functional b-cells, followed by in vivo transplantation, or hPSC differentiation in vitro towards pancreatic progenitors, which are transplanted for in vivo maturation. However, complete maturity of the hPSC-derived b-cells in vitro has been difficult to achieve. We have derived a pancreatic progenitor population from hPSCs that expresses high levels of pancreatic and duodenal homeobox 1 (Pdx1), the master transcription factor associated with the pancreatic lineage, as well as a 250-fold increase in neurogenin 3 (Ngn3) and an 800-fold increase in NK2 homeobox 2 (Nkx2.2) expression, signifying endocrine commitment of pancreatic progenitors. To model organ formation and model epithelial-mesenchymal interactions, our lab is also developing organoid models to mimic the environment experienced by endocrine progenitors as they aggregate to form the fetal islets. A model of islet development would provide a useful tool to study the mechanisms behind endocrine differentiation and islet formation.
Our preliminary organoids models using the pancreatic ductal carcinoma line, PANC1, has shown that aggregation under certain conditions can induce the expression of endocrine markers. The translation of this system to hPSC-derived progenitors, we hypothesize, will allow for the study of the migration of endocrine progenitors and islet formation.