Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo

• Published in: Nature biotechnology 2008-04, Vol.26 (4), p.443-452
• Main Authors: Richardson, Mike, Young, Holly, Kadoya, Kuniko, Baetge, Emmanuel E, Kelly, Olivia G, Carpenter, Melissa K, Smart, Nora G, Bang, Anne G, Eliazer, Susan, D'Amour, Kevin A, Agulnick, Alan D, Kroon, Evert, Martinson, Laura A, Cunningham, Justine
• Format: Article
• Language: English
• Subjects: Agriculture; Animals; Bioinformatics; Biological and medical sciences; Biomedical and Life Sciences; Biomedical Engineering/Biotechnology; Biomedicine; Biotechnology; Cell Culture Techniques - trends; Cell Differentiation; Cell Proliferation; Cells, Cultured; Diabetes; Drug therapy; Embryonic stem cells; Embryonic Stem Cells - cytology; Embryonic Stem Cells - metabolism; Embryonic Stem Cells - transplantation; Embryos; Endoderm - cytology; Endoderm - metabolism; Fundamental and applied biological sciences. Psychology; Glucose; Glucose - metabolism; Health. Pharmaceutical industry; Humans; Hyperglycemia; Industrial applications and implications. Economical aspects; Insulin; Insulin - metabolism; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - transplantation; Life Sciences; Mice; Miscellaneous; Pancreas; Pancreas, Artificial - trends; Pancreatic beta cells; Proinsulin; Rodents; Stem cells; Tissue Engineering - trends
• ISSN: 1087-0156; 1546-1696
• DOI: 10.1038/nbt1393

Development of a cell therapy for diabetes would be greatly aided by a renewable supply of human β-cells. Here we show that pancreatic endoderm derived from human embryonic stem (hES) cells efficiently generates glucose-responsive endocrine cells after implantation into mice. Upon glucose stimulation of the implanted mice, human insulin and C-peptide are detected in sera at levels similar to those of mice transplanted with ∼3,000 human islets. Moreover, the insulin-expressing cells generated after engraftment exhibit many properties of functional β-cells, including expression of critical β-cell transcription factors, appropriate processing of proinsulin and the presence of mature endocrine secretory granules. Finally, in a test of therapeutic potential, we demonstrate that implantation of hES cell–derived pancreatic endoderm protects against streptozotocin-induced hyperglycemia. Together, these data provide definitive evidence that hES cells are competent to generate glucose-responsive, insulin-secreting cells.