Title of project

Investigating the regenerative capacity of the pancreas to restore functional islet mass in diabetes.

Abstract

This project addresses a critical feature of type 1 diabetes diabetes: the loss of functional insulin-producing islet cells. Recent research has indicated a potential strategy in harnessing an inherent endogenous regenerative capacity to restore islet functionality. We hypothesise that functional islet cells can be regenerated by reactivating dormant pancreatic progenitors residing within the ductal cell niche, using a clinically approved drug that targets the Enhancer-of-Zeste-Homolog 2 enzyme, as demonstrated in human exocrine tissue from donors and cell lines (Nature STTT and Clinical Epigenetics). Preliminary data using three-dimensional organoid models created from human pancreatic ductal cells, have underlined the importance of the cellular scaffolding on the islet differentiation. However, the spatial and molecular signature of these dormant progenitor cells remain largely uncharacterised in humans, hampering the understanding of their translational use to give rise to insulin-producing tissue endogenously. By detailing their localisation in human tissue and monitoring their endocrine differentiation and islet formation within the ductal microenvironment, the project will answer key questions concerning the regenerative capacity of the pancreas and the developmental processes of islet regeneration. The proposal bridges expertise from four research institutions and transplant units from Denmark, Australia and England in a collaborative effort to provide an understanding of the benefits and limitations to an induced regenerative approach in human donors with and without type 1 diabetes: ex vivo in pancreatic tissue sections from the nPOD biobank; ex vivo tissue culture of isolated exocrine tissue from transplant centres in Australia and England; and in vitro using an in-house organoid scaffolding model in research laboratories in Australia and Denmark.