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A Rezania, JE Bruin, MJ Riedel, M Mojibian, A Asadi, J Xu, R Gauvin, K Narayan, F Karanu, JJ O'Neil, Z Ao, GL Warnock and TJ Kieffer
Abstract
Diabetes is a chronic debilitating disease that results from insufficient production of insulin from pancreatic β-cells. Islet cell replacement can effectively treat diabetes but is currently severely limited by the reliance upon cadaveric donor tissue. We have developed a protocol to efficiently differentiate commercially available human embryonic stem cells (hESCs) in vitro into a highly enriched PDX1+ pancreatic progenitor cell population that further develops in vivo to mature pancreatic endocrine cells. Immature pancreatic precursor cells were transplanted into immunodeficient mice with streptozotocin-induced diabetes, and glycemia was initially controlled with exogenous insulin. As graft-derived insulin levels increased over time, diabetic mice were weaned from exogenous insulin and human C-peptide secretion was eventually regulated by meal and glucose challenges. Similar differentiation of pancreatic precursor cells was observed after transplant in immunodeficient rats. Throughout the in vivo maturation period hESC-derived endocrine cells exhibited gene and protein expression profiles that were remarkably similar to the developing human fetal pancreas. Our findings support the feasibility of using differentiated hESCs as an alternative to cadaveric islets for treating patients with diabetes.
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Concepts
Glucose, Cell, Pancreas, Stem cell, Islets of Langerhans, Cellular differentiation, Embryonic stem cell, Insulin
MeSH headings
Animals, Cell Differentiation, Cell Line, Diabetes Mellitus, Experimental, Embryonic Stem Cells, Homeodomain Proteins, Humans, Insulin, Insulin-Secreting Cells, Male, Mice, Pancreas, Proprotein Convertases, Rats, Stem Cells, Trans-Activators
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