| First Author | Furuya F | Year | 2013 |
| Journal | J Biol Chem | Volume | 288 |
| Issue | 22 | Pages | 16155-66 |
| PubMed ID | 23595988 | Mgi Jnum | J:315258 |
| Mgi Id | MGI:6829925 | Doi | 10.1074/jbc.M112.438192 |
| Citation | Furuya F, et al. (2013) Ligand-bound thyroid hormone receptor contributes to reprogramming of pancreatic acinar cells into insulin-producing cells. J Biol Chem 288(22):16155-66 |
| abstractText | One goal of diabetic regenerative medicine is to instructively convert mature pancreatic exocrine cells into insulin-producing cells. We recently reported that ligand-bound thyroid hormone receptor alpha (TRalpha) plays a critical role in expansion of the beta-cell mass during postnatal development. Here, we used an adenovirus vector that expresses TRalpha driven by the amylase 2 promoter (AdAmy2TRalpha) to induce the reprogramming of pancreatic acinar cells into insulin-producing cells. Treatment with l-3,5,3-triiodothyronine increases the association of TRalpha with the p85alpha subunit of phosphatidylinositol 3-kinase (PI3K), leading to the phosphorylation and activation of Akt and the expression of Pdx1, Ngn3, and MafA in purified acinar cells. Analyses performed with the lectin-associated cell lineage tracing system and the Cre/loxP-based direct cell lineage tracing system indicate that newly synthesized insulin-producing cells originate from elastase-expressing pancreatic acinar cells. Insulin-containing secretory granules were identified in these cells by electron microscopy. The inhibition of p85alpha expression by siRNA or the inhibition of PI3K by LY294002 prevents the expression of Pdx1, Ngn3, and MafA and the reprogramming to insulin-producing cells. In immunodeficient mice with streptozotocin-induced hyperglycemia, treatment with AdAmy2TRalpha leads to the reprogramming of pancreatic acinar cells to insulin-producing cells in vivo. Our findings suggest that ligand-bound TRalpha plays a critical role in beta-cell regeneration during postnatal development via activation of PI3K signaling. |
