1. Stem cells to make β cells and
recreate human Type 1 diabetes
JDRF Spring Research Briefing
Douglas Melton
Dept of Stem Cell and Regenerative
Biology
Harvard Stem Cell Institute
Howard Hughes Medical Institute
5. Type I diabetes
1. Loss of beta cells – insulin dependence
(relevance for some Type II diabetics)
Make more β cells
2. Autoimmune attack of β cells
Analyze the development of the immune
attack to induce tolerance
6. Human islets for transplantation
Photo: Dr. Gordon Weir, Joslin Diabetes Center
7. How to make pancreatic β cells
1. Directed differentiation of embryonic
stem or iPS cells
2. Direct reprogramming
3. Control β cell replication
8. 2 ways to make more to β cells
Directed differentiation β cells
ES / iPS cell
Growth factors,
Definitive endoderm Co-culture
Sox 17 Foregut
FoxA2 Pancreas
Pdx1
Endocrine
Chemical screening
Ngn3
β cell
9. High content chemical screens
on hES and mES cells
Starting ES
population 5K Chemical DMSO control Hit compound
library 4 days Sox17
O’night incubation staining
incubation
HTS image-based
analysis
Lee Rubin
HSCI
21. Type I diabetes
1. Loss of beta cells – insulin dependence
Make more β cells
2. Autoimmune attack of β cells
Analyze the development of the immune
attack to induce tolerance
25. Directed differentiation β cells
2 ways to make more to thymic
epithelial cells
ES / iPS cell
Definitive endoderm
Pharyngeal foregut
Pax 9 Thymic epithelial progenitor
FoxN1
Thymic epithelial cell
26. Recapitulating human Type 1 diabetes in a
humanized mouse
DiPS
Thymic Epithelial Cells Blood Cells Pancreatic Beta Cells
George Daley
NOD, SCID, IL2-rγ
Dale Greiner
Lenny Schultz
• Function of cells population
• Disease onset and progression
• Treatments or cure
28. Harvard Stem Cell Institute
Dept of Stem Cell and Regenerative
Biology
Howard Hughes Medical Institute
Malgorzata Borowiak Yuval Dor
Shuibing Chen Dale Greiner
Adriana Tajonar Lenny Shultz
Rene Maehr Lee Rubin
Saranya Purushothaman Stuart Schreiber
Joe Zhou George Daley
Derrick Rossi
Marc Vidal