Growth factors and medium hyperglycemia induce Sox9+ ductal cell differentiation into ß cells in mice with reversal of diabetes.
Proc Natl Acad Sci U S A
; 113(3): 650-5, 2016 Jan 19.
Article
em En
| MEDLINE
| ID: mdl-26733677
ABSTRACT
We previously reported that long-term administration of a low dose of gastrin and epidermal growth factor (GE) augments ß-cell neogenesis in late-stage diabetic autoimmune mice after eliminating insulitis by induction of mixed chimerism. However, the source of ß-cell neogenesis is still unknown. SRY (sex-determining region Y)-box 9(+) (Sox9(+)) ductal cells in the adult pancreas are clonogenic and can give rise to insulin-producing ß cells in an in vitro culture. Whether Sox9(+) ductal cells in the adult pancreas can give rise to ß cells in vivo remains controversial. Here, using lineage-tracing with genetic labeling of Insulin- or Sox9-expressing cells, we show that hyperglycemia (>300 mg/dL) is required for inducing Sox9(+) ductal cell differentiation into insulin-producing ß cells, and medium hyperglycemia (300-450 mg/dL) in combination with long-term administration of low-dose GE synergistically augments differentiation and is associated with normalization of blood glucose in nonautoimmune diabetic C57BL/6 mice. Short-term administration of high-dose GE cannot augment differentiation, although it can augment preexisting ß-cell replication. These results indicate that medium hyperglycemia combined with long-term administration of low-dose GE represents one way to induce Sox9(+) ductal cell differentiation into ß cells in adult mice.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ductos Pancreáticos
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Gastrinas
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Diferenciação Celular
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Meios de Cultura
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Diabetes Mellitus Experimental
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Fator de Crescimento Epidérmico
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Células Secretoras de Insulina
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Hiperglicemia
Limite:
Animals
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article