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

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.

journal_name

Diabetes

journal_title

Diabetes

authors

Dhawan S,Dirice E,Kulkarni RN,Bhushan A

doi

10.2337/db15-1331

subject

Has Abstract

pub_date

2016-05-01 00:00:00

pages

1208-18

issue

5

eissn

0012-1797

issn

1939-327X

pii

db15-1331

journal_volume

65

pub_type

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