Mellitus results from failure pancreatic islets leading to an increase in morbidity and mortality. Mechanistic studies of this disease are hindered by low availability, high variabiliy and the cost of human islets. Our recent advances have led to the first successful method to generate mature, glucose sensing- insulin secreting b cells from human embryonic stem (ES) cells in vitro. This method, and its application using human iPS cells, provides a virtually unlimited supply of standardized human ? cells. Moreover, as the ? cells can be prepared from patient iPS cells, normal and diseased states can be analyzed. This advance provides a renewable source of b cells for cell replacement therapy for insulin dependent diabetics and the opportunity to perform rigorous disease modeling to identify therapeutic targets for all diabetics. Despite these advances, challenges remain. Robust, sensitive and routine technologies to assess ? cell function are lacking. Further, it is unlikely that b cells by themselves will recapitulate the complex biology involved in islet function. As such, the proposed research aims to combine approaches in stem cell and islet biology with tissue engineering to design, build and test new technologies for generating human islets in vitro and assessing their function in microfluidic devices. Using reverse engineering principles we will design and build a bio-inspired microfluidic chip that supports the survival and function of cell clusters containing b cells. This "islet chip" design will enable rigorous and sensitive evaluation of ? cell function that goes beyond current technologies. This chip will also provide a platform to evaluate human cadaveric islets by quantifying their functional variability. In parallel, we seek to generate whole islets i vitro using a combination of top-down and bottom-up tissue engineering approaches. Endocrine progenitors from human stem cells (ES and iPS) will be introduced to a chip designed to screen a combination of substrates, matrixes and mechanical forces to identify a niche that supports differentiation to islet-like structures with all endocrine cell types. The resulting stem cell-derved islets will be evaluated in our islet chip to describe the functional differences between these ES-islets, bcells alone and cadaveric islets. Finally, we will use these technologies for disease modeling and drug screening by generating healthy and diseased islets from iPS cells representing different disease states (healthy, type 1, type 2 diabetes, MODY) and evaluate the function and response of these islets to diabetes drugs. These studies will provide validated technologies that will increase our understanding of diabetes and speed development of new therapies.

Public Health Relevance

The development of new therapies for diabetes (type 1 and type 2) would benefit from a renewable source of human islets and a test system that allows for rapid and reproducible assays for islet function. These two advances will be developed together to improve drug testing, better understand the causes of diabetes while aiming for new therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
High Impact Research and Research Infrastructure Cooperative Agreement Programs—Multi-Yr Funding (UC4)
Project #
1UC4DK104165-01
Application #
8813382
Study Section
Special Emphasis Panel (ZDK1-GRB-9 (O1))
Program Officer
Abraham, Kristin M
Project Start
2014-09-20
Project End
2019-06-30
Budget Start
2014-09-20
Budget End
2019-06-30
Support Year
1
Fiscal Year
2014
Total Cost
$6,844,182
Indirect Cost
$1,750,803
Name
Harvard University
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138