Functional Testing of Candidate HSC-derived Islet Cells
Contact PI: Maike Sander
Ben Stanger, PhD, University of Pennsylvania
Christopher Newgard, PhD, Duke University
Recent years have seen rapid advances in development of in vitro culture methods for guiding differentiation of human embryonic stem cells towards pancreatic islet cells. Several laboratories have recently described in vitro stem cell culture methods that yield insulin-expressing cells with some ability to secrete insulin in response to glucose. Gaining deeper knowledge of the functional properties of stem cell derived islet cells produced from the top source laboratories in the country would serve as a valuable benchmark for progress towards development of a renewable source of human islet cells for broad-based research applications. Here we seek to test the extent to which stem-cell-derived human cells resemble human islets in their responses to various agents that are known to stimulate insulin secretion and cell replication in normal human islets.
This is a collaborative project involving the groups of Drs. Ben Stanger, Paul Gadue and Ken Zaret and colleagues at University of Pennsylvania, Dr. Maike Sander at UCSD, and Drs. Hans Hohmeier and Chris Newgard at Duke. This team will execute the following specific aims: two large, separate batches of islet-like clusters from human embryonic stem cells (SC), one batch in the laboratory of Dr. Sander and one in the laboratories of Drs. Stanger, Gadue and Zaret. Each of the batches will be shipped to Drs. Hohmeier and Newgard at Duke for functional testing; 2) To treat the SC-derived human islet-like clusters with two small molecules that consistently activate primary human islet cell proliferation and protect against ER stress. The goal is to determine if the small molecules also have these biological effects in the SC-derived cells; 3) To perform insulin secretion studies in the SC-derived islet cells in response to stimulatory glucose and other insulin secretagogues in both the static incubation and cell perifusion formats. This collaborative work could be an important step in addressing a major bottleneck in islet research, which is the paucity and functional heterogeneity of cadaveric human islet cell aliquots.
Opportunity Pool Project Sponsored by CHIB.