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.
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We thank Ole Madsen (Hagedorn Research Institute), Christopher Wright (Vanderbilt University), Roland Stein (Vanderbilt University) and Patrick Collombat (Max-Planck Institute) for antibody reagents; Michael McCaffery at John Hopkins University for performing the TEM analyses. The CyT203 and CyT49 cell lines were derived with partial funding from the Juvenile Diabetes Research Foundation.
The authors are full-time employees at Novocell Inc., a biotechnology company.
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Kroon, E., Martinson, L., Kadoya, K. et al. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol 26, 443–452 (2008). https://doi.org/10.1038/nbt1393
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