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Treating diet-induced diabetes and obesity with human embryonic stem cell-derived pancreatic progenitor cells and antidiabetic drugs.

Bruin JE, Saber N, Braun N, Fox JK, Mojibian M, Asadi A, Drohan C, O'Dwyer S, Rosman-Balzer DS, Swiss VA, Rezania A, Kieffer TJ - Stem Cell Reports (2015)

Bottom Line: Human embryonic stem cell (hESC)-derived pancreatic progenitor cells effectively reverse hyperglycemia in rodent models of type 1 diabetes, but their capacity to treat type 2 diabetes has not been reported.All combination therapies rapidly improved body weight and co-treatment with either sitagliptin or metformin improved hyperglycemia after only 12 weeks.Therefore, a stem cell-based therapy may be effective for treating type 2 diabetes, particularly in combination with antidiabetic drugs.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular and Cellular Medicine, Department of Cellular & Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.

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The Morphology of Macroencapsulated hESC-Derived Pancreatic Endocrine Cells Is Similar in Grafts from Mice Fed a LFD or HFD(A, B, and D–I) Representative immunofluorescent images of Theracyte devices at 29 weeks post-transplantation from mice fed 10% fat or 60% fat diets.(A) The majority of hESC-derived cells within devices from both diet groups were endocrine cells. The expression of synaptophysin (endocrine marker, red), CK19 (ductal marker, green), trypsin (exocrine marker, blue), and DAPI (nuclear marker, white) is shown. Scale bars, 100 μm.(B) The endocrine compartment was mainly composed of cells expressing either insulin (red, guinea pig antibody), glucagon (green, rabbit antibody), or somatostatin (blue, Ms antibody); scale bars, 100 μm. Higher-magnification images are shown in (E); scale bars, 50 μm.(C) The percentage of cells (% of DAPI+ nuclei) within devices that were immunoreactive for insulin (insulin+), glucagon (glucagon+), or both hormones (ins+/gcg+) was quantified in grafts from mice fed 10% fat or 45%–60% fat diets. ∗p < 0.05, two-tailed t test. Data are represented as mean ± SEM and data points from individual mice are also shown.(D) Example of graft tissue from the 60% fat diet group with a region of endocrine cells that expressed both insulin and glucagon (white arrows); scale bars, 25 μm.(F–I) The majority of insulin-positive cells (INS, red) show a mature beta cell phenotype, including co-expression of key beta cell transcription factors (green): (F) PDX1, (G) NKX2.2, (H) NKX6.1, and (I) MAFA; scale bars, 50 μm. See also Figure S2 and Tables S2 and S4.
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fig4: The Morphology of Macroencapsulated hESC-Derived Pancreatic Endocrine Cells Is Similar in Grafts from Mice Fed a LFD or HFD(A, B, and D–I) Representative immunofluorescent images of Theracyte devices at 29 weeks post-transplantation from mice fed 10% fat or 60% fat diets.(A) The majority of hESC-derived cells within devices from both diet groups were endocrine cells. The expression of synaptophysin (endocrine marker, red), CK19 (ductal marker, green), trypsin (exocrine marker, blue), and DAPI (nuclear marker, white) is shown. Scale bars, 100 μm.(B) The endocrine compartment was mainly composed of cells expressing either insulin (red, guinea pig antibody), glucagon (green, rabbit antibody), or somatostatin (blue, Ms antibody); scale bars, 100 μm. Higher-magnification images are shown in (E); scale bars, 50 μm.(C) The percentage of cells (% of DAPI+ nuclei) within devices that were immunoreactive for insulin (insulin+), glucagon (glucagon+), or both hormones (ins+/gcg+) was quantified in grafts from mice fed 10% fat or 45%–60% fat diets. ∗p < 0.05, two-tailed t test. Data are represented as mean ± SEM and data points from individual mice are also shown.(D) Example of graft tissue from the 60% fat diet group with a region of endocrine cells that expressed both insulin and glucagon (white arrows); scale bars, 25 μm.(F–I) The majority of insulin-positive cells (INS, red) show a mature beta cell phenotype, including co-expression of key beta cell transcription factors (green): (F) PDX1, (G) NKX2.2, (H) NKX6.1, and (I) MAFA; scale bars, 50 μm. See also Figure S2 and Tables S2 and S4.

Mentions: At 29 weeks post-transplantation, hESC-derived grafts had similar or significantly higher levels of islet-related genes compared with human islets and there were no significant differences between grafts from mice fed LFDs or HFDs (Figure 3). The majority of cells within the harvested devices were immunoreactive for the endocrine marker synaptophysin, and a small proportion expressed the ductal marker CK19. Trypsin-positive exocrine cells were rarely observed (Figure 4A). The grafts were largely composed of cells expressing insulin, glucagon, or somatostatin (Figures 4B and 4E), and the percentage of mono-hormonal insulin-positive and glucagon-positive cells was similar between diet groups (Figure 4C). However, we did note a minor but significantly higher percentage of cells that were immunoreactive for both insulin and glucagon in the HFD grafts compared with LFD grafts (Figures 4C and 4D). Aside from these rare polyhormonal cells, exposure to HFDs did not appear to generally influence the maturation state of hESC-derived insulin-secreting cells: the majority of insulin-positive cells in all transplant recipients co-expressed PDX1 (Figure 4F), NKX2.2 (Figure 4G), NKX6.1 (Figure 4H), and MAFA (Figure 4I) at 29 weeks post-transplantation.


Treating diet-induced diabetes and obesity with human embryonic stem cell-derived pancreatic progenitor cells and antidiabetic drugs.

Bruin JE, Saber N, Braun N, Fox JK, Mojibian M, Asadi A, Drohan C, O'Dwyer S, Rosman-Balzer DS, Swiss VA, Rezania A, Kieffer TJ - Stem Cell Reports (2015)

The Morphology of Macroencapsulated hESC-Derived Pancreatic Endocrine Cells Is Similar in Grafts from Mice Fed a LFD or HFD(A, B, and D–I) Representative immunofluorescent images of Theracyte devices at 29 weeks post-transplantation from mice fed 10% fat or 60% fat diets.(A) The majority of hESC-derived cells within devices from both diet groups were endocrine cells. The expression of synaptophysin (endocrine marker, red), CK19 (ductal marker, green), trypsin (exocrine marker, blue), and DAPI (nuclear marker, white) is shown. Scale bars, 100 μm.(B) The endocrine compartment was mainly composed of cells expressing either insulin (red, guinea pig antibody), glucagon (green, rabbit antibody), or somatostatin (blue, Ms antibody); scale bars, 100 μm. Higher-magnification images are shown in (E); scale bars, 50 μm.(C) The percentage of cells (% of DAPI+ nuclei) within devices that were immunoreactive for insulin (insulin+), glucagon (glucagon+), or both hormones (ins+/gcg+) was quantified in grafts from mice fed 10% fat or 45%–60% fat diets. ∗p < 0.05, two-tailed t test. Data are represented as mean ± SEM and data points from individual mice are also shown.(D) Example of graft tissue from the 60% fat diet group with a region of endocrine cells that expressed both insulin and glucagon (white arrows); scale bars, 25 μm.(F–I) The majority of insulin-positive cells (INS, red) show a mature beta cell phenotype, including co-expression of key beta cell transcription factors (green): (F) PDX1, (G) NKX2.2, (H) NKX6.1, and (I) MAFA; scale bars, 50 μm. See also Figure S2 and Tables S2 and S4.
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fig4: The Morphology of Macroencapsulated hESC-Derived Pancreatic Endocrine Cells Is Similar in Grafts from Mice Fed a LFD or HFD(A, B, and D–I) Representative immunofluorescent images of Theracyte devices at 29 weeks post-transplantation from mice fed 10% fat or 60% fat diets.(A) The majority of hESC-derived cells within devices from both diet groups were endocrine cells. The expression of synaptophysin (endocrine marker, red), CK19 (ductal marker, green), trypsin (exocrine marker, blue), and DAPI (nuclear marker, white) is shown. Scale bars, 100 μm.(B) The endocrine compartment was mainly composed of cells expressing either insulin (red, guinea pig antibody), glucagon (green, rabbit antibody), or somatostatin (blue, Ms antibody); scale bars, 100 μm. Higher-magnification images are shown in (E); scale bars, 50 μm.(C) The percentage of cells (% of DAPI+ nuclei) within devices that were immunoreactive for insulin (insulin+), glucagon (glucagon+), or both hormones (ins+/gcg+) was quantified in grafts from mice fed 10% fat or 45%–60% fat diets. ∗p < 0.05, two-tailed t test. Data are represented as mean ± SEM and data points from individual mice are also shown.(D) Example of graft tissue from the 60% fat diet group with a region of endocrine cells that expressed both insulin and glucagon (white arrows); scale bars, 25 μm.(F–I) The majority of insulin-positive cells (INS, red) show a mature beta cell phenotype, including co-expression of key beta cell transcription factors (green): (F) PDX1, (G) NKX2.2, (H) NKX6.1, and (I) MAFA; scale bars, 50 μm. See also Figure S2 and Tables S2 and S4.
Mentions: At 29 weeks post-transplantation, hESC-derived grafts had similar or significantly higher levels of islet-related genes compared with human islets and there were no significant differences between grafts from mice fed LFDs or HFDs (Figure 3). The majority of cells within the harvested devices were immunoreactive for the endocrine marker synaptophysin, and a small proportion expressed the ductal marker CK19. Trypsin-positive exocrine cells were rarely observed (Figure 4A). The grafts were largely composed of cells expressing insulin, glucagon, or somatostatin (Figures 4B and 4E), and the percentage of mono-hormonal insulin-positive and glucagon-positive cells was similar between diet groups (Figure 4C). However, we did note a minor but significantly higher percentage of cells that were immunoreactive for both insulin and glucagon in the HFD grafts compared with LFD grafts (Figures 4C and 4D). Aside from these rare polyhormonal cells, exposure to HFDs did not appear to generally influence the maturation state of hESC-derived insulin-secreting cells: the majority of insulin-positive cells in all transplant recipients co-expressed PDX1 (Figure 4F), NKX2.2 (Figure 4G), NKX6.1 (Figure 4H), and MAFA (Figure 4I) at 29 weeks post-transplantation.

Bottom Line: Human embryonic stem cell (hESC)-derived pancreatic progenitor cells effectively reverse hyperglycemia in rodent models of type 1 diabetes, but their capacity to treat type 2 diabetes has not been reported.All combination therapies rapidly improved body weight and co-treatment with either sitagliptin or metformin improved hyperglycemia after only 12 weeks.Therefore, a stem cell-based therapy may be effective for treating type 2 diabetes, particularly in combination with antidiabetic drugs.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular and Cellular Medicine, Department of Cellular & Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.

Show MeSH
Related in: MedlinePlus