Biological and Biomaterial Approaches for Improved Islet Transplantation

Narang, Ajit S.; Mahato, Ram I.

doi:10.1124/pr.58.2.6

Cited by 172 publications

(163 citation statements)

References 535 publications

(603 reference statements)

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“…Non-viral vectors offer the major advantage of high clinical safety and lack of vector-mediated immunogenicity, but they are significantly disadvantaged by their low-efficiency transduction (10-20%) in pancreatic islets (Narang & Mahato 2006). On the other hand, viral vectors offer the advantage of high-efficiency transduction but are limited by their unstable expression, need for repeated administration and stimulation of the immune system (Muruve et al 1999).…”

Section: Apoptosis In Islet Transplantation: the Role For Pro-inflammmentioning

confidence: 99%

IGF2: an endocrine hormone to improve islet transplant survival

Hughes¹,

Rojas-Canales²,

Drogemuller³

et al. 2014

Journal of Endocrinology

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In the week following pancreatic islet transplantation, up to 50% of transplanted islets are lost due to apoptotic cell death triggered by hypoxic and pro-inflammatory cytokinemediated cell stress. Thus, therapeutic approaches designed to protect islet cells from apoptosis could significantly improve islet transplant success. IGF2 is an anti-apoptotic endocrine protein that inhibits apoptotic cell death through the mitochondrial (intrinsic pathway) or via antagonising activation of pro-inflammatory cytokine signalling (extrinsic pathway), in doing so IGF2 has emerged as a promising therapeutic molecule to improve islet survival in the immediate post-transplant period. The development of novel biomaterials coated with IGF2 is a promising strategy to achieve this. This review examines the mechanisms mediating islet cell apoptosis in the peri-and post-transplant period and aims to identify the utility of IGF2 to promote islet survival and enhance long-term insulin independence rates within the setting of clinical islet transplantation.

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Section: Apoptosis In Islet Transplantation: the Role For Pro-inflammmentioning

confidence: 99%

IGF2: an endocrine hormone to improve islet transplant survival

Hughes¹,

Rojas-Canales²,

Drogemuller³

et al. 2014

Journal of Endocrinology

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“…TNF-α is a critical player in the inflammatory response in acute pancreatitis [12] and has been reported to be involved in pancreas graft dysfunction [13]. Circulating TNF-α is increased in obesity [14] and has been implicated as a causative factor in obesity-associated insulin resistance and the pathogenesis of type 2 diabetes [15,16].…”

Section: Introductionmentioning

confidence: 99%

TNF-α acutely upregulates amylin expression in murine pancreatic beta cells

Cai

Wang

et al. 2010

Diabetologia

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Aims/hypothesis Amylin, a secretory protein mainly produced by pancreatic beta cells, is elevated in the circulation of patients with diseases related to acute and chronic inflammation, including acute pancreatitis, pancreas graft rejection, obesity and insulin resistance. TNF-α is involved in these disorders. We investigated the effect of TNF-α on amylin levels and the underlying mechanisms, using murine pancreatic beta cell line MIN6 and pancreatic islets. Methods Amylin, proinsulin and prohormone convertase 1/3, 2 (Pc1/3, Pc2 [also known as Pcsk1/3 and Pcsk2, respectively]) mRNA levels, and amylin promoter and nuclear factor κB (NF-κB) activation were examined by real-time PCR and luciferase reporter assay, respectively. Amylin protein level and mitogen-activated protein kinase phosphorylation were detected by western blot. Activator protein 1 (AP1) activation was examined by electrophoretic mobility shift assay (EMSA).Results TNF-α acutely induced amylin expression at the transcriptional level and increased proamylin and the intermediate form of amylin in MIN6 cells and islets. However, it had no effect on proinsulin, Pc1/3 and Pc2 expression. Studies with (1) MIN6 cells treated with inhibitors of MEK1/2, c-Jun-N-terminal kinase (JNK) or protein kinase CK PKC ð z Þ, (2) MIN6 cells expressing a c-Jun-dominant negative construct and (3) islets from Fos knockout mice demonstrated that TNF-α induced amylin expression through the PKC z Àextracellular signal-regulated kinase (ERK)/JNK pathways. EMSA showed that PKC z , JNK and ERK1/2 were involved in TNF-α-induced AP1 activation, suggesting that TNF-α induces murine amylin expression through the PKC z ÀERK1=2ÀAP1 and PKC z À JNKÀAP1 pathways. Further studies showed that TNF-α also induced murine amylin expression through the phosphatidylinositol 3 kinase-NF-κB signalling pathway and enhanced human amylin promoter activation through NF-κB and AP1. Conclusions/interpretation TNF-α acutely induces amylin gene expression in beta cells through multiple signalling pathways, possibly contributing to amylin elevation in acute inflammation-related pancreatic disorders.

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“…3 A major reason underlying the requirement for multiple donors and problems with early graft function is thought to be the high rate of b-cell death that occurs during the isolation, purification and posttransplant period. Many factors likely contribute to early b-cell death and primary graft non-function, including exposure of the transplanted cells to a toxic milieu of hyperglycemia, cytokines and immunosuppressive drugs; [4][5][6][7] ischemic damage prior to graft revascularization; 8,9 and mechanical stress during the transplantation procedure. 10 New approaches that decrease the number of islets needed for successful transplantation or enhance graft function in the immediate post-transplant period could have a major impact on the long-term success of islet transplants and XIap inhibition of b-cell apoptosis reduces the number of islets required to restore euglycemia in a syngeneic islet transplantation model annette plesner, 1, * Galina soukhatcheva, 1 Robert G. Korneluk 2 and c. Bruce Verchere the number of diabetic recipients that could benefit from the procedure.…”

Section: Introductionmentioning

confidence: 99%