Effects of Micro-Encapsulation on Morphology and Endocrine Function of Cryopreserved Neonatal Porcine Islet-Like Cell Clusters

Murakami, Makoto; Satou, Hirohide; Kimura, Toshihisa; Kobayashi, Taizou; Yamaguchi, Akio; Nakagawara, Gizou; Iwata, Hiroo

doi:10.1097/00007890-200010270-00003

Cited by 22 publications

(17 citation statements)

References 21 publications

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“…However, our results are consistent with the study of Murakami et al (22), in which glucose levels were normalized 3-4 weeks after transplantation of 8,000 encapsulated NPCCs in the peritoneal cavity of diabetic mice. It is noteworthy that the study of Rayat et al (13) found that only 2,000 encapsulated NPCCs could reverse diabetes in nude mice, with this result being better than that obtained with similar numbers of unencapsulated NPCCs.…”

Section: Discussionsupporting

confidence: 93%

“…Lanza et al (21) showed that transplantation of microencapsulated adult pig islets, enclosed in poly-L-lysine (PLL)-coated alginate capsules, could normalize the blood glucose levels of STZ-induced diabetic mice for 10 weeks. Furthermore, Murakami et al (22) showed that encapsulation with agarose prolongs the survival of NPCCs for 6 -8 weeks after transplantation in BALB/c mice. Sun et al (4) reported long-term survival of microencapsulated adult porcine islets transplanted into STZ-diabetic Cynomolgus monkeys, although these results have yet to be reproduced.…”

Section: Discussionmentioning

confidence: 99%

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Survival and Maturation of Microencapsulated Porcine Neonatal Pancreatic Cell Clusters Transplanted into Immunocompetent Diabetic Mice

et al. 2003

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Differentiation and maturation of porcine neonatal pancreatic cell clusters (NPCCs) microencapsulated in barium alginate were assessed after transplantation into immunocompetent mice. Microencapsulated NPCCs were transplanted into the peritoneal cavity of streptozocin-induced diabetic B6AF1 mice (n ‫؍‬ 32). The microcapsules were removed at 2, 6, and 20 weeks and examined for cellular overgrowth, insulin content, and insulin secretory responses to glucose and glucose with theophylline. The differentiation, maturation, and proliferation of the ␤-cells in the NPCCs were assessed by immunohistochemistry. Blood glucose levels were normalized in 81% of the animals that received a transplant and remained normal until termination of the experiments at 20 weeks. Hyperglycemic blood glucose levels after explantation of the capsules confirmed the function of the encapsulated NPCCs. Insulin content of the encapsulated NPCCs was increased 10-fold at 20 weeks after transplantation compared with pretransplantation levels. A 3.2-fold increase of the ratio of the ␤-cell area to the total cellular area was observed at 20 weeks, demonstrating the maturation of NPCCs into ␤-cells. A s a result of recent progress (1), there is increased interest in islet transplantation as a potential therapy for type 1 diabetes. However, two major barriers must be overcome before islet transplantation can be provided for more patients: 1) the limited availability of human pancreatic tissue and 2) the need for permanent immunosuppression to prevent graft rejection and autoimmunity (2). Xenogeneic islets from pigs and cows (3-5) have been considered as potential sources of islets for transplantation. Many factors favor the use of pigs: the similar structure of porcine and human insulin, the comparable glucose levels, and that both pigs and humans are omnivores. Islet cells can be isolated in large numbers from adult (6 -9) or neonatal pigs (10,11). However, adult pig islets have proved to be difficult to isolate and tend to fare poorly in tissue culture, which has limited their use. Neonatal pancreatic cell clusters (NPCCs) contain a high proportion of islet precursor cells, can be maintained in culture, and differentiate into ␤-cells after transplantation (11). Naked (10,12) or microencapsulated NPCCs (13) have been shown to restore normoglycemia after transplantation into streptozotocin (STZ)-diabetic nude mice.The concept of a bioartificial pancreas, consisting of islets enclosed within immunobarrier membranes, provides a potential way to overcome the need for immunosuppression. Our group recently developed a promising encapsulation method that uses highly purified alginate cross-linked with BaCl 2 , without a separate permselective barrier, which protects islets against allorejection and autoimmunity (14). The aims of this study were to assess the protective capacity of simple barium-alginate capsules in a xenotransplantation model of NPCCs transplanted into STZ-induced diabetic immunocompetent mice and then to evaluate the growth, maturation, a...

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Survival and Maturation of Microencapsulated Porcine Neonatal Pancreatic Cell Clusters Transplanted into Immunocompetent Diabetic Mice

et al. 2003

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“…30 However, the specific cell of origin of these tumors remains to be identified. 7,31 In addition, the loss of endocrine phenotype, function and survival following islet isolation 6,9,12,13,32,33 and transplantation [9][10][11] has been implicated in the failure of islet grafts to restore euglycemia in diabetic transplant recipients. In the present study, we extend our previous work on an in vitro model of islet-to-duct transformation 5,8,14 to the char- acterization of the opposing signaling events that underlie this phenotypic switch.…”

Section: Discussionmentioning

confidence: 99%

“…These changes in the differentiated state of isolated islets prior to and following transplantation are suggested to lead to the failure of islets to restore glucohomeostasis in a significant population of transplant recipients. [9][10][11][12][13] This model could, therefore, provide valuable insight into the control of adult islet cell differentiation.…”

Section: Introductionmentioning

confidence: 99%

Signals for death and differentiation: a two-step mechanism for in vitro transformation of adult islets of Langerhans to duct epithelial structures

Lipsett

Hazrati

et al. 2003

Cell Death Differ

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Phenotypic change of adult pancreatic islets has been implicated in the development of certain pancreatic cancers and in islet transplant failure. The aim of this study was to characterize intracellular events that mediate changes in adult islet phenotype. Using an in vitro islet-to-duct transformation model, canine islets were induced to undergo phenotypic transformation to duct-like epithelial structures through a two-stage process. Stage one was characterized by widespread islet cell apoptosis associated with the formation of cavitary spaces within the islets. During this stage, c-Jun Nterminal regulated kinase (JNK) and caspase-3 activities were elevated, while extracellular signal-regulated kinase (ERK) and Akt activities were decreased. The second stage of the process was characterized by an inversion in the balance in activity between these signal transduction pathways and by a concomitant decrease in apoptosis. The transformed islets were no longer immunoreactive for islet cell hormones, but expressed the duct epithelial cell marker CK-AE1/AE3. In contrast to islet cells, these duct epithelial cells were highly proliferative. To clarify the role of the identified changes in signal transduction events, we performed additional studies using pharmacological inhibitors of enzyme activity and demonstrated that inhibition of JNK and caspase-3 activity prevented cystic transformation. Our results indicate that the balance in signaling activity between ERK/Akt and JNK/ caspase-3 appears to be an important regulator of islet cell death and differentiation.

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“…Ñüîãîäí³ àêòèâíî âåäåòüñÿ ïîøóê íîâèõ ï³ä-õîä³â äî ïðîäîâaeåííÿ òåðì³íó âèaeèâàííÿ òðàíñ-ïëàíòàòà øëÿõîì ñòâîðåííÿ éîãî îïòèìàëüíîãî ì³êðîîòî÷åííÿ [98]. Îäíèì ³ç òàêèõ ï³äõîä³â º êîìá³íîâàíà òðàíñïëàíòàö³ÿ, òîáòî îäíî÷àñíà òðàíñïëàíòàö³ÿ äâîõ ³ á³ëüøå âèä³â òêàíèí àáî êë³òèí.…”

Section: êë³í³÷íà åíäîêðèíîëîã³ÿ òà åíäîêðèííà õ³ðóðã³ÿ 1(42) 2013unclassified

Combined xenotransplantation as a method of prolonging the viability and function of the graft in the treatment of various forms of hypocorticism

Ларін¹,

Анастасій²,

Гирявенко³

et al. 2013

CE&ES

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Effects of Micro-Encapsulation on Morphology and Endocrine Function of Cryopreserved Neonatal Porcine Islet-Like Cell Clusters

Abstract: Our study suggests that micro-encapsulation is one of the useful method for cryopreserved ICC to maintain the fine morphology and effectively recover the endocrine function.

Cited by 22 publications

References 21 publications

Survival and Maturation of Microencapsulated Porcine Neonatal Pancreatic Cell Clusters Transplanted into Immunocompetent Diabetic Mice

Survival and Maturation of Microencapsulated Porcine Neonatal Pancreatic Cell Clusters Transplanted into Immunocompetent Diabetic Mice

Signals for death and differentiation: a two-step mechanism for in vitro transformation of adult islets of Langerhans to duct epithelial structures

Combined xenotransplantation as a method of prolonging the viability and function of the graft in the treatment of various forms of hypocorticism

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