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

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

SUBMITTER: Dhawan S 

PROVIDER: S-EPMC4839200 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature