| First Author | Dhawan S | Year | 2016 |
| Journal | Diabetes | Volume | 65 |
| Issue | 5 | Pages | 1208-18 |
| PubMed ID | 26936960 | Mgi Jnum | J:249640 |
| Mgi Id | MGI:5923211 | Doi | 10.2337/db15-1331 |
| Citation | Dhawan S, et al. (2016) Inhibition of TGF-beta Signaling Promotes Human Pancreatic beta-Cell Replication. Diabetes 65(5):1208-18 |
| abstractText | Diabetes is associated with loss of functional pancreatic beta-cells, and restoration of beta-cells is a major goal for regenerative therapies. Endogenous regeneration of beta-cells via beta-cell replication has the potential to restore cellular mass; however, pharmacological agents that promote regeneration or expansion of endogenous beta-cells have been elusive. The regenerative capacity of beta-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-beta (TGF-beta) signaling via Smad3 integrates with the trithorax complex to activate and maintain Ink4a expression to prevent beta-cell replication. Importantly, inhibition of TGF-beta signaling can result in repression of the Ink4a/Arf locus, resulting in increased beta-cell replication in adult mice. Furthermore, small molecule inhibitors of the TGF-beta pathway promote beta-cell replication in human islets transplanted into NOD-scid IL-2Rg(null) mice. These data reveal a novel role for TGF-beta signaling in the regulation of the Ink4a/Arf locus and highlight the potential of using small molecule inhibitors of TGF-beta signaling to promote human beta-cell replication. |
