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1.
Diabetes ; 55(7): 1930-8, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16804060

RESUMO

The ATP-sensitive K(+) channel (K(ATP) channel) in pancreatic beta-cells is a critical regulator in insulin secretion. We previously reported that transgenic mice expressing a dominant-negative form (Kir6.2G132S) of Kir6.2, a subunit of the K(ATP) channel, specifically in beta-cells develop severe hyperglycemia in adults (8 weeks of age). In this study, we conducted a long-term investigation of the phenotype of these transgenic mice. Surprisingly, hyperglycemia was spontaneously improved with concomitant improvement of pancreatic insulin content in the transgenic mice at >25 weeks of age. Insulin-positive cells and pancreatic duodenal homeobox 1 (PDX1)-positive cells both were clearly increased in the older compared with the younger transgenic mice. Interestingly, cells labeled with the lectin Dolichos biflorus agglutinin (DBA), a potential indicator of uncommitted pancreatic epithelial/ductal cells, were detected in the islets of the transgenic mice but not in those of wild-type mice. In addition, a subset of the DBA-labeled cells was positive for PDX1, insulin, glucagon, somatostatin, or pancreatic polypeptide. Moreover, some of the DBA-labeled cells were also positive for a proliferating cell marker. These results show that the Kir6.2G132S transgenic mouse is a useful model for studying beta-cell regeneration and that DBA-labeled cells participate in the process.


Assuntos
Hiperglicemia/prevenção & controle , Ilhotas Pancreáticas/fisiologia , Canais de Potássio Corretores do Fluxo de Internalização/fisiologia , Substituição de Aminoácidos , Animais , Apoptose , Glicemia/metabolismo , Teste de Tolerância a Glucose , Glicina , Marcação In Situ das Extremidades Cortadas , Insulina/sangue , Camundongos , Camundongos Transgênicos , Canais de Potássio Corretores do Fluxo de Internalização/genética , Serina
3.
Proc Natl Acad Sci U S A ; 102(42): 15116-21, 2005 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-16210247

RESUMO

Although several studies have suggested that insulin-secreting cells can be generated in vitro from cells residing in adult exocrine pancreas, neither the origin of these cells nor their precise insulin secretory properties was obtained. We show here that insulin-secreting cells can be derived from adult mouse pancreatic exocrine cells by suspension culture in the presence of EGF and nicotinamide. The frequency of insulin-positive cells was only 0.01% in the initial preparation and increased to approximately 5% in the culture conditions. Analysis by the Cre/loxP-based direct cell lineage tracing system indicates that these newly made cells originate from amylase/elastase-expressing pancreatic acinar cells. Insulin secretion is stimulated by glucose, sulfonylurea, and carbachol, and potentiation by glucagon-like peptide-1 also occurs. Insulin-containing secretory granules are present in these cells. In addition, we found that the enzymatic dissociation of pancreatic acini itself leads to activation of EGF signaling, and that inhibition of EGF receptor kinase blocks the transdifferentiation. These data demonstrate that pancreatic acinar cells can transdifferentiate into insulin-secreting cells with secretory properties similar to those of native pancreatic beta cells, and that activation of EGF signaling is required in such transdifferentiation.


Assuntos
Linhagem da Célula , Insulina/metabolismo , Pâncreas Exócrino/citologia , Animais , Diferenciação Celular/fisiologia , Células Cultivadas , Quelantes/metabolismo , Ditizona/metabolismo , Fator de Crescimento Epidérmico/metabolismo , Perfilação da Expressão Gênica , Genes Reporter , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pâncreas Exócrino/fisiologia , Transdução de Sinais/fisiologia
4.
Dev Dyn ; 228(4): 664-71, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14648843

RESUMO

Embryonic stem cells have the potential to give rise to all cell lineages when introduced into the early embryo. They also give rise to a limited number of different cell types in vitro in specialized culture systems. In this study, we established a culture system in which a structure consisting of lens, neural retina, and pigmented retina was efficiently induced from embryonic stem cells. Refractile cell masses containing lens and neural retina were surrounded by retinal pigment epithelium layers and, thus, designated as eye-like structures. Developmental processes required for eye development appear to proceed in this culture system, because the formation of the eye-like structures depended on the expression of Pax6, a key transcription factor for eye development. The present culture system opens up the possibility of examining early stages of eye development and also of producing cells for use in cellular therapy for various diseases of the eye.


Assuntos
Embrião de Mamíferos/citologia , Regulação da Expressão Gênica no Desenvolvimento , Cristalino/embriologia , Retina/embriologia , Células-Tronco/citologia , Animais , Diferenciação Celular , Linhagem Celular , Células Cultivadas , Proteínas do Olho , Proteínas de Fluorescência Verde , Proteínas de Homeodomínio/fisiologia , Imuno-Histoquímica , Proteínas Luminescentes/metabolismo , Camundongos , Microscopia de Fluorescência , Neurônios/metabolismo , Fator de Transcrição PAX6 , Fatores de Transcrição Box Pareados , Proteínas Repressoras , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo
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