In Vitro and In Vivo Improvement of Islet Survival Following Treatment with Nerve Growth Factor

Miao, Gang; Mace, John; Kirby, Michael A.; Hopper, Andrew; Peverini, Ricardo; Chinnock, Richard; Shapiro, James; Hathout, Eba

doi:10.1097/01.tp.0000200320.16723.b3

Cited by 36 publications

(38 citation statements)

References 31 publications

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“…[19][20][21][22] However, we observed that NGF-treated islets led to worse graft function following intraportal islet transplantation when compared with untreated islets. Considerably more NGF-treated islets were nonviable (TUNEL-positive and necrotic), and revascularization of viable (TUNEL-negative and not necrotic) grafts was not enhanced several days after transplantation.…”

Section: Discussioncontrasting

confidence: 37%

“…[19][20][21][22] We previously demonstrated that treatment of pancreatic islets with NGF improved their quality and viability. Revascularization and survival of islets transplanted under the kidney capsule were improved by NGF.…”

Section: Introductionmentioning

confidence: 99%

“…Revascularization and survival of islets transplanted under the kidney capsule were improved by NGF. 20 Moreover, islets were efficiently transplanted in vascularized chambers based on the neurovascular support from the femoral artery, vein and nerve, in the presence of a gelatin sponge scaffold with NGF. 23 However, the usefulness of NGF in intraportal islet transplantation was still unknown.…”

Section: Introductionmentioning

confidence: 99%

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Nerve growth factor is associated with islet graft failure following intraportal transplantation

Saito

Chan

Sakata

et al. 2012

Islets

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Nerve growth factor (NGF) has recently been recognized as an angiogenic factor with an important regulatory role in pancreatic b-cell function. We previously showed that treatment of pancreatic islets with NGF improved their quality and viability. Revascularization and survival of islets transplanted under the kidney capsule were improved by NGF. However, the usefulness of NGF in intraportal islet transplantation was not previously tested. To resolve this problem, we transplanted syngeneic islets (360 islet equivalents per recipient) cultured with or without NGF into the portal vein of streptozotocin-induced diabetic BALB/c mice. Analysis revealed that 44.4% (4/9) of control and 12.5% (1/8) of NGF-treated mice attained normoglycemia (# 200 mg/dL) (p = 0.195). NGF-treated islets led to worse graft function (area under the curve of intraperitoneal glucose tolerance tests (IPGTT) on post-operative day (POD) 30, control; 35,800 ± 3,960 min*mg/dl, NGF-treated; 47,900 ± 3,220 min*mg/dl: *p = 0.0348). NGF treatment of islets was also associated with increased graft failure [the percentage of TdT-mediated dUTP-biotin nick-end labeling (TUNEL)-positive and necrotic transplanted islets on POD 5, control; 23.8% (5/21), NGF-treated; 52.9% (9/17): p = 0.0650] following intraportal islet transplantation. Nonviable (TUNEL-positive and necrotic) islets in both groups expressed vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1a (HIF-1a). On the other hand, viable (TUNEL-negative and not necrotic) islets in both groups did not express VEGF and HIF-1a. In the present study, pre-transplant NGF treatment was associated with impaired survival and angiogenesis of intraportal islet grafts. The effect of NGF on islet transplantation may significantly vary according to the transplant site.

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Section: Discussioncontrasting

confidence: 37%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Nerve growth factor is associated with islet graft failure following intraportal transplantation

Saito

Chan

Sakata

et al. 2012

Islets

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“…Ngfb promotes b-cell survival 33,34 and increases islet morphogenesis. 35 RT-PCR analysis revealed lower Ngfb expression in BBdp rats (Figure 6d), which could further contribute to the reduced capacity for b-cell survival and islet expansion.…”

Section: Decreased Ngfb and Pdx1 Gene Expressionmentioning

confidence: 99%

Increased islet neogenesis without increased islet mass precedes autoimmune attack in diabetes-prone rats

Kauri¹,

Wang²,

Patrick

et al. 2007

Laboratory Investigation

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We reported previously that young BioBreeding diabetes-prone (BBdp) rats display increased neogenic extra-islet insulin þ clusters (EICs, o4 insulin þ cells) without an increase in b-cell mass. Therefore, we investigated the possibility that abnormal islet expansion occurs in BBdp rats before the appearance of islet inflammation. Islet expansion was analyzed in pancreata from 14 to 45 day BBdp and control (BioBreeding control, BBc) rats using immunohistochemistry, morphometry, laser capture microdissection and reverse transcriptase-PCR. mRNA expression for Neurogenin-3, a developmental marker of endocrine progenitors, was three-fold greater in EIC of weanling BBdp and BBc rats compared with islet cells. With increasing age (14-30 days), Neurogenin-3 expression decreased in EIC and increased in islets. In BBdp rats, EIC number and b-cell proliferation within EIC was greater compared with BBc animals; apoptosis did not differ. The area of small and medium islets in BBdp rats was greater than BBc rats between 14 and 30 days, but this did not result in increased total islet area or b-cell mass. In addition, the number and area of very large islets was low at 45 days. The frequency of proliferating b-cells decreased with increasing islet size in BBdp but was constant in BBc rats. Cell cycle analysis of islets revealed more G1 cells and fewer G2 cells in BBdp rats. The ratio of cyclinD2/Cdkn1a, genes that respectively promote or inhibit cell cycle progression, was decreased in BBdp islets. These results suggest that despite increased islet neogenesis, the capacity for islet expansion in diabetes-prone rats is compromised possibly due to decreased proliferative capacity with increasing islet size associated with a partial block at the G1/S cell cycle boundary in islet cells.

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“…Examples of such peptides include hepatocyte growth factor, [15][16][17] calcitonin gene-related peptide 18 and nerve growth factor. 19 Using adenoviral vectors, Narang et al 20 have shown that ex-vivo transfection of two genes that target different islet insults has an additive effect on transplanted islet cell survival, as compared with the transfection of either gene alone. Therefore, it is conceivable that the strategy that was used in the present work is applied using cells that are transfected with two or more different genes, or combining two or several types of cells overexpressing different genes.…”

Section: Discussionmentioning

confidence: 99%

Co-encapsulation of bioengineered IGF-II-producing cells and pancreatic islets: effect on beta-cell survival

et al. 2011

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Insulin-like growth factor-II (IGF-II) has been shown to promote pancreatic b-cell survival. We evaluated the effect of co-encapsulating islets and bioengineered IGF-II-producing cells on islet cell survival. IGF-II or green fast protein (GFP) genes were transferred into TM4 cells, and purified using a neomycin resistance gene, leading to pure cell cultures (TM4-IGF-II or TM4-GFP) with a stable overexpression of the transferred gene. Islets were co-encapsulated with TM4-IGF-II or TM4-GFP, or encapsulated alone in alginate microcapsules. Rat and mouse islet cell survival was studied in vitro and in vivo, respectively. After 12 days in culture, islet viability (dual staining, acridine orange/propidium iodide) was 83% with TM4-IGF-II, compared with 51% (Po0.05) and 41% (Po0.001) with TM4-GFP and islets alone, respectively. The study of islet necrotic centers and the evaluation of islet function, using the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) assay, yielded similar results. From 125 days after transplantation, more diabetic mice maintained normoglycemia when they were transplanted with islets co-encapsulated with TM4-IGF-II (4/7). A significant difference for the maintenance of normoglycemia was observed between recipients of islets co-encapsulated with TM4-IGF-II versus islets alone (P¼0.023), or with TM4-GFP (P¼0.048). In conclusion, the co-encapsulation of islets with bioengineered IGF-II-producing cells promotes islet cell survival.

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In Vitro and In Vivo Improvement of Islet Survival Following Treatment with Nerve Growth Factor

Abstract: The above data suggest potential advantages of NGF for islet survival following transplantation. This neurotrophic approach may prove beneficial in human islet transplantation.

Cited by 36 publications

References 31 publications

Nerve growth factor is associated with islet graft failure following intraportal transplantation

Nerve growth factor is associated with islet graft failure following intraportal transplantation

Increased islet neogenesis without increased islet mass precedes autoimmune attack in diabetes-prone rats

Co-encapsulation of bioengineered IGF-II-producing cells and pancreatic islets: effect on beta-cell survival

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