Abstract
Understanding the mechanisms by which cells sense and respond to injury is central to developing therapies to enhance tissue regeneration. Previously, we showed that pancreatic injury consisting of acinar cell damage+β-cell ablation led to islet cell transdifferentiation. Here, we report that the molecular mechanism for this requires activating protease-activated receptor-2 (PAR2), a G-protein-coupled receptor. PAR2 modulation was sufficient to induce islet cell transdifferentiation in the absence of β-cells. Its expression was modulated in an islet cell type-specific manner in murine and human type 1 diabetes (T1D). In addition to transdifferentiation, PAR2 regulated β-cell apoptosis in pancreatitis. PAR2’s role in regeneration is broad, as mice lacking PAR2 had marked phenotypes in response to injury in the liver and in digit regeneration following amputation. These studies provide a pharmacologically relevant target to induce tissue regeneration in a number of diseases, including T1D.
| Original language | English |
|---|---|
| Article number | e2452 |
| Journal | Cell Death and Disease |
| Volume | 7 |
| Issue number | 11 |
| DOIs | |
| State | Published - 3 Nov 2016 |
Bibliographical note
Publisher Copyright:© The Author(s) 2016.
Funding
Acknowledgements. This work was supported by the Sanford Children’s Health Research Center, BetaBat (in the Framework Program 7 of the European Community), CIRM grant TG2-01162, and a German Research Foundation fellowship to PK. We are grateful for assistance from SBP Core personnel Guillermina Garcia (Histopathology) and Xiayu (Stacy) Huang (statistics; bioinfor-matics). We acknowledge nPOD and NDRI for providing human tissues.
| Funders | Funder number |
|---|---|
| Sanford Children’s Health Research Center | |
| National Cancer Institute | P30CA030199 |
| California Institute for Regenerative Medicine | TG2-01162 |
| Deutsche Forschungsgemeinschaft |
