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Extracellular Matrix and Growth Factors Improve the Efficacy of Intramuscular Islet Transplantation.

Tsuchiya H, Sakata N, Yoshimatsu G, Fukase M, Aoki T, Ishida M, Katayose Y, Egawa S, Unno M - PLoS ONE (2015)

Bottom Line: The following three groups were evaluated: islets without treatment (islets-only group), islets embedded in ECM with growth factors (Matrigel group), and islets embedded in ECM without growth factors [growth factor-reduced (GFR) Matrigel group].The viability and insulin-releasing function of islets cultured for 96 h were significantly improved in Matrigel and GFR Matrigel groups compared with the islets-only group.On histological examination, significantly decreased numbers of TdT-mediated deoxyuridine triphosphate-biotin nick end labeling-positive islet cells and significantly increased numbers of Ki67-positive cells were observed in the Matrigel and GFR Matrigel groups at POD 3.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Tohoku University, Sendai, Japan.

ABSTRACT

Background: The efficacy of intramuscular islet transplantation is poor despite being technically simple, safe, and associated with reduced rates of severe complications. We evaluated the efficacy of combined treatment with extracellular matrix (ECM) and growth factors in intramuscular islet transplantation.

Methods: Male BALB/C mice were used for the in vitro and transplantation studies. The following three groups were evaluated: islets without treatment (islets-only group), islets embedded in ECM with growth factors (Matrigel group), and islets embedded in ECM without growth factors [growth factor-reduced (GFR) Matrigel group]. The viability and insulin-releasing function of islets cultured for 96 h were significantly improved in Matrigel and GFR Matrigel groups compared with the islets-only group.

Results: Blood glucose and serum insulin levels immediately following transplantation were significantly improved in the Matrigel and GFR Matrigel groups and remained significantly improved in the Matrigel group at postoperative day (POD) 28. On histological examination, significantly decreased numbers of TdT-mediated deoxyuridine triphosphate-biotin nick end labeling-positive islet cells and significantly increased numbers of Ki67-positive cells were observed in the Matrigel and GFR Matrigel groups at POD 3. Peri-islet revascularization was most prominent in the Matrigel group at POD 14.

Conclusions: The efficacy of intramuscular islet transplantation was improved by combination treatment with ECM and growth factors through the inhibition of apoptosis, increased proliferation of islet cells, and promotion of revascularization.

No MeSH data available.


Changes in the blood glucose concentrations, serum insulin level, and IPGTT following transplantation.Transplantation outcomes were evaluated by the measurement of BG and serum insulin levels and GTTs. (A) BG levels were significantly improved in islets embedded in ECM (both Matrigel and GFR Matrigel groups) compared with the islets-only group. BG levels were significantly lower in the Matrigel group compared with the GFR Matrigel group at POD 28. (B) Comparison of changes in blood glucose concentrations between intramuscular transplantation in the Matrigel group and the intraportal transplantation group. No significant differences were observed in changes in blood glucose concentration between intramuscular transplantation in the Matrigel group and the intrahepatic transplantation group. (C) Serum insulin levels were significantly increased in the GFR Matrigel and Matrigel groups compared with the islets-only group, and levels in the Matrigel were significantly higher than those in the GFR Matrigel group at POD 28. (D) IPGTT AUC values in both the GFR Matrigel and Matrigel groups were significantly lower than those in the islets-only group. AUC, area under the curve; BG, blood glucose; ECM, extracellular matrix; GFR, growth factor reduced; GTT, glucose tolerance test; IPGTT, intraperitoneal glucose tolerance test; POD, postoperative day.
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pone.0140910.g004: Changes in the blood glucose concentrations, serum insulin level, and IPGTT following transplantation.Transplantation outcomes were evaluated by the measurement of BG and serum insulin levels and GTTs. (A) BG levels were significantly improved in islets embedded in ECM (both Matrigel and GFR Matrigel groups) compared with the islets-only group. BG levels were significantly lower in the Matrigel group compared with the GFR Matrigel group at POD 28. (B) Comparison of changes in blood glucose concentrations between intramuscular transplantation in the Matrigel group and the intraportal transplantation group. No significant differences were observed in changes in blood glucose concentration between intramuscular transplantation in the Matrigel group and the intrahepatic transplantation group. (C) Serum insulin levels were significantly increased in the GFR Matrigel and Matrigel groups compared with the islets-only group, and levels in the Matrigel were significantly higher than those in the GFR Matrigel group at POD 28. (D) IPGTT AUC values in both the GFR Matrigel and Matrigel groups were significantly lower than those in the islets-only group. AUC, area under the curve; BG, blood glucose; ECM, extracellular matrix; GFR, growth factor reduced; GTT, glucose tolerance test; IPGTT, intraperitoneal glucose tolerance test; POD, postoperative day.

Mentions: Following syngeneic intramuscular transplantation, BG levels were significantly improved following transplantation of islets embedded in ECM (both Matrigel and GFR Matrigel) compared with the islets-only group (P = 0.0004 and 0.016; Fig 4A). The difference between Matrigel and GFR Matrigel groups gradually increased after transplantation and became prominent from POD 7. At POD 28, BG levels were significantly lower in the Matrigel group compared with the GFR Matrigel group (islets-only, 459.3 ± 66.4 mg/dl; GFR Matrigel, 342.2 ± 35.9 mg/dl; Matrigel, 220.3 ± 27.0 mg/dl; P = 0.043 for islets-only vs. GFR Matrigel; P < 0.0001 for islets-only vs. Matrigel; P = 0.022 for GFR Matrigel vs. Matrigel; Fig 4A). The proportion of mice achieving normoglycemia following transplantation was 0% in the islets-only group, 20% in the GFR Matrigel group, and 50% in the Matrigel group (P = 0.19 for islets-only vs. GFR Matrigel; P = 0.025 for islets-only vs. Matrigel; P = 0.16 for GFR Matrigel vs. Matrigel). The reason why all the groups did not reach under 200 mg/dL in BG level was because some mice that failed to reach normoglycemia had high glucose levels. The proportion of mice in the Matrigel group achieving normoglycemia following intramuscular transplantation was equal to or greater than in mice receiving intraportal transplantation of islets (Fig 4A; Table 2), with no difference observed in the change in BG concentrations between intramuscular transplantation in the Matrigel group and the intrahepatic transplantation group (P = 0.81; Fig 4B).


Extracellular Matrix and Growth Factors Improve the Efficacy of Intramuscular Islet Transplantation.

Tsuchiya H, Sakata N, Yoshimatsu G, Fukase M, Aoki T, Ishida M, Katayose Y, Egawa S, Unno M - PLoS ONE (2015)

Changes in the blood glucose concentrations, serum insulin level, and IPGTT following transplantation.Transplantation outcomes were evaluated by the measurement of BG and serum insulin levels and GTTs. (A) BG levels were significantly improved in islets embedded in ECM (both Matrigel and GFR Matrigel groups) compared with the islets-only group. BG levels were significantly lower in the Matrigel group compared with the GFR Matrigel group at POD 28. (B) Comparison of changes in blood glucose concentrations between intramuscular transplantation in the Matrigel group and the intraportal transplantation group. No significant differences were observed in changes in blood glucose concentration between intramuscular transplantation in the Matrigel group and the intrahepatic transplantation group. (C) Serum insulin levels were significantly increased in the GFR Matrigel and Matrigel groups compared with the islets-only group, and levels in the Matrigel were significantly higher than those in the GFR Matrigel group at POD 28. (D) IPGTT AUC values in both the GFR Matrigel and Matrigel groups were significantly lower than those in the islets-only group. AUC, area under the curve; BG, blood glucose; ECM, extracellular matrix; GFR, growth factor reduced; GTT, glucose tolerance test; IPGTT, intraperitoneal glucose tolerance test; POD, postoperative day.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4608691&req=5

pone.0140910.g004: Changes in the blood glucose concentrations, serum insulin level, and IPGTT following transplantation.Transplantation outcomes were evaluated by the measurement of BG and serum insulin levels and GTTs. (A) BG levels were significantly improved in islets embedded in ECM (both Matrigel and GFR Matrigel groups) compared with the islets-only group. BG levels were significantly lower in the Matrigel group compared with the GFR Matrigel group at POD 28. (B) Comparison of changes in blood glucose concentrations between intramuscular transplantation in the Matrigel group and the intraportal transplantation group. No significant differences were observed in changes in blood glucose concentration between intramuscular transplantation in the Matrigel group and the intrahepatic transplantation group. (C) Serum insulin levels were significantly increased in the GFR Matrigel and Matrigel groups compared with the islets-only group, and levels in the Matrigel were significantly higher than those in the GFR Matrigel group at POD 28. (D) IPGTT AUC values in both the GFR Matrigel and Matrigel groups were significantly lower than those in the islets-only group. AUC, area under the curve; BG, blood glucose; ECM, extracellular matrix; GFR, growth factor reduced; GTT, glucose tolerance test; IPGTT, intraperitoneal glucose tolerance test; POD, postoperative day.
Mentions: Following syngeneic intramuscular transplantation, BG levels were significantly improved following transplantation of islets embedded in ECM (both Matrigel and GFR Matrigel) compared with the islets-only group (P = 0.0004 and 0.016; Fig 4A). The difference between Matrigel and GFR Matrigel groups gradually increased after transplantation and became prominent from POD 7. At POD 28, BG levels were significantly lower in the Matrigel group compared with the GFR Matrigel group (islets-only, 459.3 ± 66.4 mg/dl; GFR Matrigel, 342.2 ± 35.9 mg/dl; Matrigel, 220.3 ± 27.0 mg/dl; P = 0.043 for islets-only vs. GFR Matrigel; P < 0.0001 for islets-only vs. Matrigel; P = 0.022 for GFR Matrigel vs. Matrigel; Fig 4A). The proportion of mice achieving normoglycemia following transplantation was 0% in the islets-only group, 20% in the GFR Matrigel group, and 50% in the Matrigel group (P = 0.19 for islets-only vs. GFR Matrigel; P = 0.025 for islets-only vs. Matrigel; P = 0.16 for GFR Matrigel vs. Matrigel). The reason why all the groups did not reach under 200 mg/dL in BG level was because some mice that failed to reach normoglycemia had high glucose levels. The proportion of mice in the Matrigel group achieving normoglycemia following intramuscular transplantation was equal to or greater than in mice receiving intraportal transplantation of islets (Fig 4A; Table 2), with no difference observed in the change in BG concentrations between intramuscular transplantation in the Matrigel group and the intrahepatic transplantation group (P = 0.81; Fig 4B).

Bottom Line: The following three groups were evaluated: islets without treatment (islets-only group), islets embedded in ECM with growth factors (Matrigel group), and islets embedded in ECM without growth factors [growth factor-reduced (GFR) Matrigel group].The viability and insulin-releasing function of islets cultured for 96 h were significantly improved in Matrigel and GFR Matrigel groups compared with the islets-only group.On histological examination, significantly decreased numbers of TdT-mediated deoxyuridine triphosphate-biotin nick end labeling-positive islet cells and significantly increased numbers of Ki67-positive cells were observed in the Matrigel and GFR Matrigel groups at POD 3.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Tohoku University, Sendai, Japan.

ABSTRACT

Background: The efficacy of intramuscular islet transplantation is poor despite being technically simple, safe, and associated with reduced rates of severe complications. We evaluated the efficacy of combined treatment with extracellular matrix (ECM) and growth factors in intramuscular islet transplantation.

Methods: Male BALB/C mice were used for the in vitro and transplantation studies. The following three groups were evaluated: islets without treatment (islets-only group), islets embedded in ECM with growth factors (Matrigel group), and islets embedded in ECM without growth factors [growth factor-reduced (GFR) Matrigel group]. The viability and insulin-releasing function of islets cultured for 96 h were significantly improved in Matrigel and GFR Matrigel groups compared with the islets-only group.

Results: Blood glucose and serum insulin levels immediately following transplantation were significantly improved in the Matrigel and GFR Matrigel groups and remained significantly improved in the Matrigel group at postoperative day (POD) 28. On histological examination, significantly decreased numbers of TdT-mediated deoxyuridine triphosphate-biotin nick end labeling-positive islet cells and significantly increased numbers of Ki67-positive cells were observed in the Matrigel and GFR Matrigel groups at POD 3. Peri-islet revascularization was most prominent in the Matrigel group at POD 14.

Conclusions: The efficacy of intramuscular islet transplantation was improved by combination treatment with ECM and growth factors through the inhibition of apoptosis, increased proliferation of islet cells, and promotion of revascularization.

No MeSH data available.