Reversal of β cell de-differentiation by a small molecule inhibitor of the TGFβ pathway

Barak Blum, Adam N. Roose, Ornella Barrandon, René Maehr, Anthony C. Arvanites, Lance S. Davidow, Jeffrey C. Davis, Quinn Peterson, Lee L. Rubin, Douglas A. Melton

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

Dysfunction or death of pancreatic β cells underlies both types of diabetes. This functional decline begins with β cell stress and de-differentiation. Current drugs for type 2 diabetes (T2D) lower blood glucose levels but they do not directly alleviate β cell stress nor prevent, let alone reverse, β cell de-differentiation. We show here that Urocortin 3 (Ucn3), a marker for mature β cells, is down-regulated in the early stages of T2D in mice and when β cells are stressed in vitro. Using an insulin expression-coupled lineage tracer, with Ucn3 as a reporter for the mature β cell state, we screen for factors that reverse β cell de-differentiation. We find that a small molecule inhibitor of TGFβ receptor I (Alk5) protects cells from the loss of key β cell transcription factors and restores a mature β cell identity even after exposure to prolonged and severe diabetes.

Original languageEnglish (US)
Pages (from-to)e02809
JournaleLife
Volume3
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Keywords

  • Alk5 inhibitor II
  • beta cells
  • cell biology
  • dedifferentiation
  • developmental biology
  • diabetes
  • human
  • mouse
  • stem cells
  • Tgf-beta
  • Ucn3

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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  • Cite this

    Blum, B., Roose, A. N., Barrandon, O., Maehr, R., Arvanites, A. C., Davidow, L. S., Davis, J. C., Peterson, Q., Rubin, L. L., & Melton, D. A. (2014). Reversal of β cell de-differentiation by a small molecule inhibitor of the TGFβ pathway. eLife, 3, e02809. https://doi.org/10.7554/eLife.02809