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Diabetes. 2016 May;65(5):1208-18. doi: 10.2337/db15-1331. Epub 2016 Mar 2.

Inhibition of TGF-β Signaling Promotes Human Pancreatic β-Cell Replication.

Author information

1
Division of Endocrinology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA.
2
Islet Cell and Regenerative Biology, Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
3
Diabetes Center, University of California, San Francisco, San Francisco, CA anil.bhushan@ucsf.edu.

Abstract

Diabetes is associated with loss of functional pancreatic β-cells, and restoration of β-cells is a major goal for regenerative therapies. Endogenous regeneration of β-cells via β-cell replication has the potential to restore cellular mass; however, pharmacological agents that promote regeneration or expansion of endogenous β-cells have been elusive. The regenerative capacity of β-cells declines rapidly with age, due to accumulation of p16(INK4a), resulting in limited capacity for adult endocrine pancreas regeneration. Here, we show that transforming growth factor-β (TGF-β) signaling via Smad3 integrates with the trithorax complex to activate and maintain Ink4a expression to prevent β-cell replication. Importantly, inhibition of TGF-β signaling can result in repression of the Ink4a/Arf locus, resulting in increased β-cell replication in adult mice. Furthermore, small molecule inhibitors of the TGF-β pathway promote β-cell replication in human islets transplanted into NOD-scid IL-2Rg(null) mice. These data reveal a novel role for TGF-β signaling in the regulation of the Ink4a/Arf locus and highlight the potential of using small molecule inhibitors of TGF-β signaling to promote human β-cell replication.

PMID:
26936960
PMCID:
PMC4839200
DOI:
10.2337/db15-1331
[Indexed for MEDLINE]
Free PMC Article

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