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Inducible VEGF expression by human embryonic stem cell-derived mesenchymal stromal cells reduces the minimal islet mass required to reverse diabetes.

Hajizadeh-Saffar E, Tahamtani Y, Aghdami N, Azadmanesh K, Habibi-Anbouhi M, Heremans Y, De Leu N, Heimberg H, Ravassard P, Shokrgozar MA, Baharvand H - Sci Rep (2015)

Bottom Line: Next, we compared functional parameters of 400 islets alone versus 200 islets co-transplanted with hESC-MSC:VEGF.Transplantation of 200 islets with hESC-MSC:VEGF showed superior function over 400 islets alone.We conclude that co-transplantation of islets with VEGF-expressing hESC-MSCs allowed for at least a 50% reduction in minimal islet mass required to reverse diabetes in mice.

View Article: PubMed Central - PubMed

Affiliation: 1] National Cell Bank, Pasteur Institute of Iran, Tehran, Iran [2] Department of Stem Cells and Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.

ABSTRACT

Unlabelled: Islet transplantation has been hampered by loss of function due to poor revascularization. We hypothesize that co-transplantation of islets with human embryonic stem cell-derived mesenchymal stromal cells that conditionally overexpress VEGF (hESC-MSC:VEGF) may augment islet revascularization and reduce the minimal islet mass required to reverse diabetes in mice. HESC-MSCs were transduced by recombinant lentiviruses that allowed conditional (Dox-regulated) overexpression of VEGF.

Hesc-msc: VEGF were characterized by tube formation assay. After co-transplantation of hESC-MSC:VEGF with murine islets in collagen-fibrin hydrogel in the omental pouch of diabetic nude mice, we measured blood glucose, body weight, glucose tolerance and serum C-peptide. As control, islets were transplanted alone or with non-transduced hESC-MSCs. Next, we compared functional parameters of 400 islets alone versus 200 islets co-transplanted with hESC-MSC:VEGF. As control, 200 islets were transplanted alone. Metabolic function of islets transplanted with hESC-MSC:VEGF significantly improved, accompanied by superior graft revascularization, compared with control groups. Transplantation of 200 islets with hESC-MSC:VEGF showed superior function over 400 islets alone. We conclude that co-transplantation of islets with VEGF-expressing hESC-MSCs allowed for at least a 50% reduction in minimal islet mass required to reverse diabetes in mice. This approach may contribute to alleviate the need for multiple donor organs per patient.

No MeSH data available.


Related in: MedlinePlus

Reduction in minimal islet mass required to reverse diabetes by co-transplantation of hESC-MSC:VEGF.(a) Blood glucose (mg/dl), (b) percentage of euglycemic mice and (c) body weight in grams (g) of mice from days 0 to 32 PAI. (d) Serum C-peptide (pM), (e) IP-GTT curve and (f) AUC of IP-GTT of mice at 30th day PAI. Values represent mean ± SD, n = 7/group. * p < 0.05, **p < 0.01, ***p < 0.005. Tx: Transplantation.
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f5: Reduction in minimal islet mass required to reverse diabetes by co-transplantation of hESC-MSC:VEGF.(a) Blood glucose (mg/dl), (b) percentage of euglycemic mice and (c) body weight in grams (g) of mice from days 0 to 32 PAI. (d) Serum C-peptide (pM), (e) IP-GTT curve and (f) AUC of IP-GTT of mice at 30th day PAI. Values represent mean ± SD, n = 7/group. * p < 0.05, **p < 0.01, ***p < 0.005. Tx: Transplantation.

Mentions: Islet function was superior in the islet200/hESC-MSC:VEGF group compared to the islet400 group. Blood glucose concentrations of mice that received islet200/hESC-MSC:VEGF were significantly lower than those of the islet400 group (p < 0.05; N = 7) at different time points (Figure 5a). Similarly, the percentage of euglycemic mice was higher in islet200/hESC-MSC:VEGF (85%) compared to islet400 group (57%)(p < 0.001; N = 7), at four weeks after transplantation (Figure 5b). The mild trend toward weight gain in islet200/hESC-MSC:VEGF group (21.5 ± 0.4 mg/day) until PAI 7 was significantly higher than in islet200 group (p < 0.01; N = 7), but was not different from islet400 group (p > 0.5; N = 7; Figure 5c).


Inducible VEGF expression by human embryonic stem cell-derived mesenchymal stromal cells reduces the minimal islet mass required to reverse diabetes.

Hajizadeh-Saffar E, Tahamtani Y, Aghdami N, Azadmanesh K, Habibi-Anbouhi M, Heremans Y, De Leu N, Heimberg H, Ravassard P, Shokrgozar MA, Baharvand H - Sci Rep (2015)

Reduction in minimal islet mass required to reverse diabetes by co-transplantation of hESC-MSC:VEGF.(a) Blood glucose (mg/dl), (b) percentage of euglycemic mice and (c) body weight in grams (g) of mice from days 0 to 32 PAI. (d) Serum C-peptide (pM), (e) IP-GTT curve and (f) AUC of IP-GTT of mice at 30th day PAI. Values represent mean ± SD, n = 7/group. * p < 0.05, **p < 0.01, ***p < 0.005. Tx: Transplantation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4377549&req=5

f5: Reduction in minimal islet mass required to reverse diabetes by co-transplantation of hESC-MSC:VEGF.(a) Blood glucose (mg/dl), (b) percentage of euglycemic mice and (c) body weight in grams (g) of mice from days 0 to 32 PAI. (d) Serum C-peptide (pM), (e) IP-GTT curve and (f) AUC of IP-GTT of mice at 30th day PAI. Values represent mean ± SD, n = 7/group. * p < 0.05, **p < 0.01, ***p < 0.005. Tx: Transplantation.
Mentions: Islet function was superior in the islet200/hESC-MSC:VEGF group compared to the islet400 group. Blood glucose concentrations of mice that received islet200/hESC-MSC:VEGF were significantly lower than those of the islet400 group (p < 0.05; N = 7) at different time points (Figure 5a). Similarly, the percentage of euglycemic mice was higher in islet200/hESC-MSC:VEGF (85%) compared to islet400 group (57%)(p < 0.001; N = 7), at four weeks after transplantation (Figure 5b). The mild trend toward weight gain in islet200/hESC-MSC:VEGF group (21.5 ± 0.4 mg/day) until PAI 7 was significantly higher than in islet200 group (p < 0.01; N = 7), but was not different from islet400 group (p > 0.5; N = 7; Figure 5c).

Bottom Line: Next, we compared functional parameters of 400 islets alone versus 200 islets co-transplanted with hESC-MSC:VEGF.Transplantation of 200 islets with hESC-MSC:VEGF showed superior function over 400 islets alone.We conclude that co-transplantation of islets with VEGF-expressing hESC-MSCs allowed for at least a 50% reduction in minimal islet mass required to reverse diabetes in mice.

View Article: PubMed Central - PubMed

Affiliation: 1] National Cell Bank, Pasteur Institute of Iran, Tehran, Iran [2] Department of Stem Cells and Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.

ABSTRACT

Unlabelled: Islet transplantation has been hampered by loss of function due to poor revascularization. We hypothesize that co-transplantation of islets with human embryonic stem cell-derived mesenchymal stromal cells that conditionally overexpress VEGF (hESC-MSC:VEGF) may augment islet revascularization and reduce the minimal islet mass required to reverse diabetes in mice. HESC-MSCs were transduced by recombinant lentiviruses that allowed conditional (Dox-regulated) overexpression of VEGF.

Hesc-msc: VEGF were characterized by tube formation assay. After co-transplantation of hESC-MSC:VEGF with murine islets in collagen-fibrin hydrogel in the omental pouch of diabetic nude mice, we measured blood glucose, body weight, glucose tolerance and serum C-peptide. As control, islets were transplanted alone or with non-transduced hESC-MSCs. Next, we compared functional parameters of 400 islets alone versus 200 islets co-transplanted with hESC-MSC:VEGF. As control, 200 islets were transplanted alone. Metabolic function of islets transplanted with hESC-MSC:VEGF significantly improved, accompanied by superior graft revascularization, compared with control groups. Transplantation of 200 islets with hESC-MSC:VEGF showed superior function over 400 islets alone. We conclude that co-transplantation of islets with VEGF-expressing hESC-MSCs allowed for at least a 50% reduction in minimal islet mass required to reverse diabetes in mice. This approach may contribute to alleviate the need for multiple donor organs per patient.

No MeSH data available.


Related in: MedlinePlus