Inhibition of TGF- Signaling Promotes Human Pancreatic -Cell Replication

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.