Presentation from Dr. Melton

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Presentation from Dr. Melton

  1. 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
  2. 2. Pancreatic islet insulin glucagon pancreatic polypeptide ghrelin somatostatin
  3. 3. Pancreatic islet insulin glucagon pancreatic polypeptide ghrelin somatostatin
  4. 4. Diabetic dog rescued by injection of islet extract Best Banting 1921
  5. 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. 6. Human islets for transplantation Photo: Dr. Gordon Weir, Joslin Diabetes Center
  7. 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. 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. 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
  10. 10. 2 compounds induce definitive endoderm (IDEs)
  11. 11. IDE compounds efficiently induce definitive endoderm mouse > 70% human >50%
  12. 12. 2 ways to make more to β cells Directed differentiation β cells ES / iPS cell Definitive endoderm Foregut Compound 1 (IDEs, 80%) Pancreas Compound 2 Endocrine ( Indolactam V, 45%) β cell Borowiak et al, Cell Stem Cell, 2009; Chen et al, Nat Chem Biol, 2009
  13. 13. Differentiation
  14. 14. cloning / iPS derivation
  15. 15. Direct reprogramming?
  16. 16. Pancreatic tissues islet vessel duct acini
  17. 17. Expression of 9 trans factors induces extra islet ins+ cells
  18. 18. Reprogrammed cells express genes essential for β cell function
  19. 19. New insulin+ cells closely resemble β cells
  20. 20. Reprogrammed cells produce and secrete insulin
  21. 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
  22. 22. Stem Cells in Regenerative Medicine
  23. 23. Key Components for Type I Diabetes
  24. 24. Diabetic patient specific induced Pluripotent Stem (DiPS) cells OCT4 SOX2 KLF4 2 days 4-6 weeks Biopsy DiPS Patient Fibroblast DiPS (10x) DiPS (40x)
  25. 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. 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
  27. 27. Patient’s perspective: Who will cure my disease? Pharma Hospital JDRF Insurance Academic Co. (Univ)
  28. 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

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