Reversal of β cell de-differentiation by a small molecule inhibitor of the TGFβ pathway.
ELIFE(2014)
摘要
Dysfunction or death of pancreatic beta cells underlies both types of diabetes. This functional decline begins with beta cell stress and de-differentiation. Current drugs for T2D lower blood glucose levels, but do not directly alleviate beta cell stress nor prevent, let alone reverse, beta cell de-differentiation. We show here that Urocortin 3 (Ucn3), a marker for mature beta cells, is down-regulated in the early stages of T2D in mice and when beta cells are stressed in vitro. Using an insulin expression-coupled lineage tracer, with Ucn3 as a reporter for the mature beta cell state, we screen for factors that reverse beta cell de-differentiation. We find that a small molecule inhibitor of TGF beta receptor I (Alk5) protects cells from the loss of key beta cell transcription factors and restores a mature beta cell identity even after exposure to prolonged and severe diabetes.
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关键词
alk5 inhibitor ii,tgf-beta,ucn3,beta cells,cell biology,dedifferentiation,developmental biology,diabetes,human,mouse,stem cells,transcription factors,tgf beta,up regulation,signal transduction,transforming growth factor beta
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