While SC-islets are less functional when first differentiated in vitro compared to isolated cadaveric islets, transplantation into mice has been shown to increase their maturation. Insulin-producing stem cell-derived islets (SC-islets) provide a virtually unlimited cell source for diabetes cell replacement therapy. See Figure S5 for additional immunofluorescent staining of hESC-derived grafts.
KELLY SHIMO NUDE PLUS
All data are presented as mean ± SEM plus individual biological replicates (n = 3 animals/group). (D) Area of synaptophysin or trypsin immunoreactivity relative to the total graft area and synaptophysin+ area relative to trypsin+ area for each graft. (C) Area of insulin (ins) or glucagon (gcg) immunoreactivity relative to total synaptophysin immunoreactivity and insulin+ area relative to glucagon+ area for each graft. DAPI nuclear staining is shown in gray in all images. Shown are (A) insulin (red) and glucagon (green) and (B) synaptophysin (red, endocrine marker) and trypsin (green, exocrine marker). Grafts from Rats Contained a Higher Proportion of Insulin:Glucagon and Synaptophysin:Trypsin Immunoreactivity Compared with Grafts from Mice (A and B) Representative immunofluorescence images of whole hESC-derived grafts (graft and kidney tissue is delineated by a dashed white line scale bars, 500 mm) and higher-magnification insets (scale bars, 100 mm) at 22 weeks post-transplantation. See Figure S4 for the human C-peptide stimulation index following meal challenges. Data are presented as mean ± SEM plus individual biological replicates in bar graphs. The black dashed line indicates the lower limit of detection for each analyte. (F) Plasma human insulin, glucagon, and GLP-1 levels at 22 or 33 weeks post-transplantation (n = 10 animals/group). For area under the curve, *p < 0.05, ***p < 0.001 two-tailed t test. For line graphs, *p < 0.05, two-way repeated-measures ANOVA with Sidak post hoc test (mouse versus rat). Human C-peptide levels are presented as (D) fold change relative to basal (red dashed line) or (E) raw values at time 0. (C-E) Blood glucose (C) and human C-peptide levels (D and E) following a 6-hr morning fast and subsequent oral glucose challenge at 21 weeks post-transplantation (n = 10-11 animals/group). *p < 0.05, paired t test (fast versus fed) #p < 0.05, one-way ANOVA with Student-Neuman-Keuls (SNK) test. Improved Glycemic Control and Better Graft Function in Rats Compared with Mice (A and B) Human C-peptide (A) and blood glucose levels (B) after an overnight fast and 45 min following an oral mixed meal between 9-32 weeks post-transplantation (n = 4-11 animals/group). Overall, hESC-derived pancreatic progenitor cells matured faster in nude rats compared with SCID-beige mice, indicating that the host recipient can greatly influence the fate of immature pancreatic progenitor cells post-transplantation. Moreover, ECM-related genes were enriched, the collagen network was denser, and blood vessels were more intricately integrated into the engrafted endocrine tissue in rats relative to mice. Grafts from rats contained a higher proportion of insulin:glucagon immunoreactivity, fewer exocrine cells, and improved expression of mature β cell markers compared with mice.
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Following the transplant, basal human C-peptide levels were consistently higher in mice compared with rats, but only rats showed robust meal- and glucose-responsive human C-peptide secretion by 19–21 weeks. To investigate the impact of the host recipient on hESC-derived pancreatic progenitor cell maturation, cells were transplanted into immunodeficient SCID-beige mice or nude rats. Pluripotent human embryonic stem cells (hESCs) are a potential source of transplantable cells for treating patients with diabetes.