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

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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 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.

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Barak Blum

Harvard Stem Cell Institute, Harvard University, Cambridge, United States

Competing interests
The authors declare that no competing interests exist.
Adam N Roose

Harvard Stem Cell Institute, Harvard University, Cambridge, United States

Competing interests
The authors declare that no competing interests exist.
Ornella Barrandon

Harvard Stem Cell Institute, Harvard University, Cambridge, United States

Competing interests
The authors declare that no competing interests exist.
René Maehr

University of Massachusetts Medical School, Worcester, United States

Competing interests
The authors declare that no competing interests exist.
Anthony C Arvanites

Harvard Stem Cell Institute, Harvard University, Cambridge, United States

Competing interests
The authors declare that no competing interests exist.
Lance S Davidow

Harvard Stem Cell Institute, Harvard University, Cambridge, United States

Competing interests
The authors declare that no competing interests exist.
Jeffrey C Davis

Harvard Stem Cell Institute, Harvard University, Cambridge, United States

Competing interests
The authors declare that no competing interests exist.
Quinn P Peterson

Harvard Stem Cell Institute, Harvard University, Cambridge, United States

Competing interests
The authors declare that no competing interests exist.
Lee L Rubin

Harvard Stem Cell Institute, Harvard University, Cambridge, United States

Competing interests
The authors declare that no competing interests exist.
Douglas A Melton

Harvard Stem Cell Institute, Harvard University, Cambridge, United States

For correspondence
dmelton@harvard.edu

Competing interests
The authors declare that no competing interests exist.

Ethics

Animal experimentation: Animal experiments were performed in compliance with the Harvard University International Animal Care and Use Committee (IACUC) guidelines (protocol #93-15).

Human subjects: Institutional review board approval for research use of human tissue was obtained from the Harvard University Faculty of Arts and Sciences. Human islets were obtained from NDRI (The National Disease Research Interchange). Donor anonymity was preserved, and the human tissue was collected under applicable regulations and guidelines regarding consent, protection of human subjects and donor confidentiality

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.