The ability to generate functional beta cells from pluripotent and adult stem cells will provide access to unlimited numbers of these cells for transplantation for the treatment of type 1 diabetes, for studying their role in disease states and for screens aimed at defining the mechanisms by which key regulators control their proliferation and maturation. This proposal outlines an integrative series of studies by seven different research groups that combine tissue engineering and cell-processing strategies with stem cell and endothelial cell biology to generate functional islet like structures with differentiated cells generated from human embryonic stem cells, human induced pluripotent stem cells (collectively referred to as pluripotent stem cells) and adult pancreatic stem cells.
The first aim focuses on defining the signaling pathways and cellular interactions that regulate development and maturation of insulin producing cells from pluripotent stem cells.
The second aim will use similar approaches to study the regulatory pathways and cell populations that control the proliferation and differentiation of a recently identified stem cell in the adult human pancreas. The experiments outlined in the third aim focus on generating endothelial progenitor populations from different sources and investigating the capacity of these populations to promote beta cell differentiation, survival and maturation. The goal of the final aim is to test the function of the cell populations and engineered tissues generated in the project by transplantation into different mouse models of diabetes. The outcome of these studies will provide important new insights into the regulation of beta cell development and maturation from stem and progenitor populations in culture. This information will be instrumental in developing strategies for the routine and large-scale production of functional beta cells in culture and for promoting regeneration from stem cells within the pancreas. These advances will pave the way to develop novel beta cell replacement and/or beta cell regeneration therapies for the treatment of type 1 diabetes.

Public Health Relevance

The goals are to study the processes that control the generation and maturation of insulin producing beta cells from pluripotent stem cells and adult pancreatic-derived stem cells. The new information generated from this work will provide the basis for establishing methods to produce unlimited numbers of beta cells for transplantation for the treatment of type 1 diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK089561-05
Application #
8717649
Study Section
Special Emphasis Panel (ZDK1-GRB-G (M3))
Program Officer
Sato, Sheryl M
Project Start
2010-09-15
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
5
Fiscal Year
2014
Total Cost
$100,000
Indirect Cost
$1,852
Name
University Health Network
Department
Type
DUNS #
208469486
City
Toronto
State
ON
Country
Canada
Zip Code
M5 2-M9
Amer, Luke D; Mahoney, Melissa J; Bryant, Stephanie J (2014) Tissue engineering approaches to cell-based type 1 diabetes therapy. Tissue Eng Part B Rev 20:455-67
Jaroch, David B; Lu, Jing; Madangopal, Rajtarun et al. (2013) Mouse and human islets survive and function after coating by biosilicification. Am J Physiol Endocrinol Metab 305:E1230-40
Ungrin, Mark D; Clarke, Geoff; Yin, Ting et al. (2012) Rational bioprocess design for human pluripotent stem cell expansion and endoderm differentiation based on cellular dynamics. Biotechnol Bioeng 109:853-66