Journal
STEM CELLS
Volume 31, Issue 11, Pages 2432-2442Publisher
WILEY-BLACKWELL
DOI: 10.1002/stem.1489
Keywords
Diabetes; Beta cells; Human embryonic stem cells; Cell therapy; Transplantation
Categories
Funding
- Michael Smith Foundation for Health Research
- JDRF postdoctoral fellowship
- CIHR postdoctoral fellowship
- CIHR Transplantation Training Program
- L'Oreal Canada for Women in Science Research Excellence Fellowship
- Stem Cell Technologies
- Canadian Institutes of Health Research (CIHR) Regenerative Medicine and Nanomedicine Initiative
- Stem Cell Network (SCN)
- Juvenile Diabetes Research Foundation (JDRF)
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Human embryonic stem cells (hESCs) are considered a potential alternative to cadaveric islets as a source of transplantable cells for treating patients with diabetes. We previously described a differentiation protocol to generate pancreatic progenitor cells from hESCs, composed of mainly pancreatic endoderm (PDX1/NKX6.1-positive), endocrine precursors (NKX2.2/synaptophysin-positive, hormone/NKX6.1-negative), and polyhormonal cells (insulin/glucagon-positive, NKX6.1-negative). However, the relative contributions of NKX6.1-negative versus NKX6.1-positive cell fractions to the maturation of functional -cells remained unclear. To address this question, we generated two distinct pancreatic progenitor cell populations using modified differentiation protocols. Prior to transplant, both populations contained a high proportion of PDX1-expressing cells (approximate to 85%-90%) but were distinguished by their relatively high (approximate to 80%) or low (approximate to 25%) expression of NKX6.1. NKX6.1-high and NKX6.1-low progenitor populations were transplanted subcutaneously within macroencapsulation devices into diabetic mice. Mice transplanted with NKX6.1-low cells remained hyperglycemic throughout the 5-month post-transplant period whereas diabetes was reversed in NKX6.1-high recipients within 3 months. Fasting human C-peptide levels were similar between groups throughout the study, but only NKX6.1-high grafts displayed robust meal-, glucose- and arginine-responsive insulin secretion as early as 3 months post-transplant. NKX6.1-low recipients displayed elevated fasting glucagon levels. Theracyte devices from both groups contained almost exclusively pancreatic endocrine tissue, but NKX6.1-high grafts contained a greater proportion of insulin-positive and somatostatin-positive cells, whereas NKX6.1-low grafts contained mainly glucagon-expressing cells. Insulin-positive cells in NKX6.1-high, but not NKX6.1-low grafts expressed nuclear MAFA. Collectively, this study demonstrates that a pancreatic endoderm-enriched population can mature into highly functional -cells with only a minor contribution from the endocrine subpopulation. Stem Cells2013;31:2432-2442
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