Abstract
The basic helix-loop-helix protein Neurogenin3 specifies precursor cells of the endocrine pancreas during embryonic development, and is thought to be absent postnatally. We have studied Ngn3 expression during in vitro generation of beta-cells from adult rat exocrine pancreas tissue treated with epidermal growth factor and leukaemia inhibitory factor. This treatment induced a transient expression of both Ngn3 and its upstream activator hepatocyte nuclear factor 6. Inhibition of EGF and LIF signalling by pharmacological antagonists of the JAK2/STAT3 pathway, or knockdown of Ngn3 by RNA interference prevented the generation of new insulin-positive cells. This study demonstrates that in vitro growth factor stimulation can induce recapitulation of an embryonic endocrine differentiation pathway in adult dedifferentiated exocrine cells. This could prove to be important for understanding the mechanism of beta-cell regeneration and for therapeutic ex vivo neogenesis of beta cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism*
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Cells, Cultured
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Gene Expression Profiling
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Gene Silencing
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Growth Substances / pharmacology
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Hepatocyte Nuclear Factor 6 / genetics
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Humans
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Insulin-Secreting Cells / cytology*
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Insulin-Secreting Cells / drug effects
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Insulin-Secreting Cells / metabolism*
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Janus Kinase 2 / metabolism*
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Lipase / metabolism
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Male
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Models, Animal
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Niacinamide / pharmacology
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Rats
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Rats, Wistar
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STAT3 Transcription Factor / metabolism*
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Signal Transduction* / drug effects
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Up-Regulation / drug effects
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Growth Substances
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Hepatocyte Nuclear Factor 6
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Nerve Tissue Proteins
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Neurog3 protein, rat
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RNA, Messenger
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STAT3 Transcription Factor
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Niacinamide
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Janus Kinase 2
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Lipase