Cell Derived Functionally Assembled Pancreatic Islets

This project research seeks to develop improved stem cell-based treatment of diabetes. The objective will be to synthesize an optimal tissue engineered islet (cells that produce insulin), with a sustained performance in maintaining blood glucose level. Transplantation of insulin-producing tissue has the potential to be a safe and simple procedure for curative treatment of diabetes, but it is acutely limited by the lack of donor islets and short term islet graft failure, which stem from a lack of control over different cell types constituting the purified islet, delayed revascularization and hypoxia leading to necrotic central cores.  These problems are further exacerbated with hyperglycemia.  The focus of the IGERT project will be to resolve the lack of islet source by using islet cell types derived from differentiated ES cells. ES cells will first be primed to differentiate insulin-producing islet-like cells using recently established protocols. Next, IGERT Trainees in the M. Yarmush (BME) laboratory will regenerate islet tissues that will closely mimic the endogenous tissue in cellular composition, patterning and vasculature (Fig. 13), using microfabrication techniques. The key features of islet architecture are: (i) patterning of different endocrine cell types relative to one-another and along the blood capillaries; and (ii) distribution of blood capillaries within the islet characterized by unidirectional “core-to-mantle” islet capillary perfusion. Trainees will recreate this architecture by printing blood capillaries using a sacrificial material, which would ultimately pave the way for revascularization after transplantation. The microfabricated capillaries will be surrounded by a layer of endothelial cells, above which the endocrine cell layer will be patterned along the direction of capillary flow. Using expertise from R. Foty (CDB), Trainees will examine how differential adhesion guides the spatial organization of mixed populations of islet cells derived from ES cells. Next, they will explore the relationship between islet topology and function. Finally, islet function will be tested as a function of topology and vascularization utilizing microfabricated scaffolds.

Fig. 13. Schematic of islet architecture. The arteriole pierces into the center of the islet and breaks into capillaries, which radially traverses the b cell core towards the a cell periphery.