详细记录  
题名:Enrichment of Human Embryonic Stem Cell-Derived NKX6.1-Expressing Pancreatic Progenitor Cells Accelerates the Maturation of Insulin-Secreting Cells In Vivo.
作者:REZANIA A; BRUIN JE; XU J; NARAYAN K; FOX JK; O'NEIL JJ; KIEFFER TJ;
来源:Stem Cells. 2013 Nov;31(11):2432-42. doi: 10.1002/stem.1489. [ IF= 0.00 ] ]
URL :10.1002/stem.1489
日期:20131203
摘要: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 beta-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
( approximately 85%-90%) but were distinguished by their relatively high (
approximately 80%) or low ( approximately 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 beta-cells with
only a minor contribution from the endocrine subpopulation. Stem Cells
2013;31:2432-2442.

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