Ligand-bound thyroid hormone receptor contributes to reprogramming of pancreatic acinar cells into insulin-producing cells
| Autor: | Hiroki Shimura, Keiichi Asami, Tetsuro Kobayashi, Sayaka Ichijo, Toyoshi Endo, Yoichi Oikawa, Kaoru Aida, Masahiro Kaneshige, Kazuya Takahashi, Fumihiko Furuya |
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| Rok vydání: | 2013 |
| Předmět: |
Maf Transcription Factors
Large Morpholines Mice Nude Mice Transgenic Nerve Tissue Proteins Acinar Cells Pancreatic alpha-Amylases Biology Biochemistry Viral vector Adenoviridae Mice Phosphatidylinositol 3-Kinases Transduction Genetic Insulin-Secreting Cells medicine Basic Helix-Loop-Helix Transcription Factors Animals Enzyme Inhibitors Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors Homeodomain Proteins Mice Inbred BALB C Thyroid hormone receptor Receptors Thyroid Hormone Cell Biology Cell Dedifferentiation Molecular biology Cell biology medicine.anatomical_structure Chromones Trans-Activators Phosphorylation PDX1 Triiodothyronine Pancreas Reprogramming Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | The Journal of biological chemistry. 288(22) |
| ISSN: | 1083-351X |
| Popis: | 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 α (TRα) plays a critical role in expansion of the β-cell mass during postnatal development. Here, we used an adenovirus vector that expresses TRα driven by the amylase 2 promoter (AdAmy2TRα) to induce the reprogramming of pancreatic acinar cells into insulin-producing cells. Treatment with l-3,5,3-triiodothyronine increases the association of TRα with the p85α 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 p85α 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 AdAmy2TRα leads to the reprogramming of pancreatic acinar cells to insulin-producing cells in vivo. Our findings suggest that ligand-bound TRα plays a critical role in β-cell regeneration during postnatal development via activation of PI3K signaling. |
| Databáze: | OpenAIRE |
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