Transdifferentiation of human islets to pancreatic ductal cells in collagen matrix culture

Yuan, Songyang; Rosenberg, Lawrence; Paraskevas, Steven; Agapitos, Despina; Duguid, W. P.

doi:10.1046/j.1432-0436.1996.6110067.x

Cited by 106 publications

(87 citation statements)

References 38 publications

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“…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. Until now, the mechanisms underlying phenotypic changes in adult pancreatic islets have not been well understood.…”

Section: Discussionmentioning

confidence: 52%

“…29 Having already demonstrated that type-1 collagen is necessary for islet-to-duct transformation, 5,14 and since this process appears to be associated with an increase in Akt activity, we sought to examine the independent effect of type-1 rat tail collagen on Akt activation in adult islets immediately after culture. Compared to freshly isolated islets maintained overnight in basal media alone, the activity of Akt in islets cultured overnight in type-1 collagen with basal media was two-fold greater (Figure 11), suggesting that some of the changes in Akt activity during islet-to-duct transformation may be due to the presence of type-1 collagen.…”

Section: Signal Transduction Events During Islet-to-duct Transformationmentioning

confidence: 99%

“…5 and cultured in Dulbecco's modified Eagle medium (DMEM/F12) (GIBCO, Burlington, ON, Canada) supplemented with 10% fetal bovine serum (FBS), epithelial growth factor (EGF) (100 ng/ml) (Sigma, St Louis, MO, USA) and cholera toxin (CT) (100 ng/ml) (Sigma, MO, USA). Approximately 3000 islets equivalents (IEQ) per group per time point were used.…”

Section: Islet Cell Culturementioning

confidence: 99%

“…1 In comparison, it is well known that other pancreatic cells, the acinar and ductal cells, exhibit plasticity. [2][3][4] While recent studies have begun to explore the potential of adult islet plasticity, [5][6][7] the cellular and molecular events that regulate this process remain to be elucidated. 8 An appropriate model for the study of islet plasticity will provide an understanding of mechanisms underlying adult islet cell differentiation.…”

Section: Introductionmentioning

confidence: 99%

“…5,14 In this model, isolated islets are embedded into a type-1 collagen matrix and supplemented with a defined media. This phenotypic change appears to involve a two-stage process entailing islet cell loss and a change in cell phenotype.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

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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