title: Ligand-bound thyroid hormone receptor contributes to reprogramming of pancreatic acinar cells into insulin-producing cells.
abstract: 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.
authors.affiliation: Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo-shi, Yamanashi 409-3898, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Furuya
authors.forename: Hiroki
authors.initials: H
authors.lastname: Shimura
authors.forename: Keiichi
authors.initials: K
authors.lastname: Asami
authors.forename: Sayaka
authors.initials: S
authors.lastname: Ichijo
authors.forename: Kazuya
authors.initials: K
authors.lastname: Takahashi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kaneshige
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Oikawa
authors.forename: Kaoru
authors.initials: K
authors.lastname: Aida
authors.forename: Toyoshi
authors.initials: T
authors.lastname: Endo
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Kobayashi
mesh_terms: D061354:Acinar Cells / Q000166:cytology / Q000378:metabolism*; D000256:Adenoviridae; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics; D054337:Cell Dedifferentiation; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D051473:Maf Transcription Factors, Large / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008822:Mice, Transgenic; D009025:Morpholines / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D055292:Pancreatic alpha-Amylases / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics; D014161:Transduction, Genetic; D014284:Triiodothyronine / Q000494:pharmacology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002867:Chromones; D004791:Enzyme Inhibitors; D018398:Homeodomain Proteins; D051473:Maf Transcription Factors, Large; D009025:Morpholines; D009419:Nerve Tissue Proteins; D055292:Pancreatic alpha-Amylases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011988:Receptors, Thyroid Hormone; D015534:Trans-Activators; D014284:Triiodothyronine; C485160:Mafa protein, mouse; C084010:pancreatic and duodenal homeobox 1 protein; C486336:Neurog1 protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C524800:Amy2a5 protein, mouse
keywords: Diabetes; Insulin; Pancreas; Phosphatidylinositol 3-Kinase; Thyroid Hormone