title: Impact of Sox9 dosage and Hes1-mediated Notch signaling in controlling the plasticity of adult pancreatic duct cells in mice.
abstract: In the adult pancreas, there has been a long-standing dispute as to whether stem/precursor populations that retain plasticity to differentiate into endocrine or acinar cell types exist in ducts. We previously reported that adult Sox9-expressing duct cells are sufficiently plastic to supply new acinar cells in Sox9-IRES-CreERT2 knock-in mice. In the present study, using Sox9-IRES-CreERT2 knock-in mice as a model, we aimed to analyze how plasticity is controlled in adult ducts. Adult duct cells in these mice express less Sox9 than do wild-type mice but Hes1 equally. Acinar cell differentiation was accelerated by Hes1 inactivation, but suppressed by NICD induction in adult Sox9-expressing cells. Quantitative analyses showed that Sox9 expression increased with the induction of NICD but did not change with Hes1 inactivation, suggesting that Notch regulates Hes1 and Sox9 in parallel. Taken together, these findings suggest that Hes1-mediated Notch activity determines the plasticity of adult pancreatic duct cells and that there may exist a dosage requirement of Sox9 for keeping the duct cell identity in the adult pancreas. In contrast to the extended capability of acinar cell differentiation by Hes1 inactivation, we obtained no evidence of islet neogenesis from Hes1-depleted duct cells in physiological or PDL-induced injured conditions.
authors: 1] Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan [2] Department of Clinical Application, Center for iPS cell Research and Application, Kyoto University, Kyoto, Japan.
authors: Shinichi
authors: S
authors: Hosokawa
authors: 1] Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan [2] Department of Clinical Application, Center for iPS cell Research and Application, Kyoto University, Kyoto, Japan.
authors: Kenichiro
authors: K
authors: Furuyama
authors: 1] Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan [2] Department of Clinical Application, Center for iPS cell Research and Application, Kyoto University, Kyoto, Japan.
authors: Masashi
authors: M
authors: Horiguchi
authors: 1] Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan [2] Department of Clinical Application, Center for iPS cell Research and Application, Kyoto University, Kyoto, Japan.
authors: Yoshiki
authors: Y
authors: Aoyama
authors: 1] Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan [2] Department of Clinical Application, Center for iPS cell Research and Application, Kyoto University, Kyoto, Japan.
authors: Kunihiko
authors: K
authors: Tsuboi
authors: 1] Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan [2] Department of Clinical Application, Center for iPS cell Research and Application, Kyoto University, Kyoto, Japan.
authors: Morito
authors: M
authors: Sakikubo
authors: 1] Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan [2] Department of Clinical Application, Center for iPS cell Research and Application, Kyoto University, Kyoto, Japan.
authors: Toshihiko
authors: T
authors: Goto
authors: 1] Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan [2] Department of Clinical Application, Center for iPS cell Research and Application, Kyoto University, Kyoto, Japan.
authors: Koji
authors: K
authors: Hirata
authors: 1] Department of Clinical Application, Center for iPS cell Research and Application, Kyoto University, Kyoto, Japan [2] Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors: Wataru
authors: W
authors: Tanabe
authors: Department of Clinical Application, Center for iPS cell Research and Application, Kyoto University, Kyoto, Japan.
authors: Yasuhiro
authors: Y
authors: Nakano
authors: Department of Orthopaedics, Gifu University, Gifu, Japan.
authors: Haruhiko
authors: H
authors: Akiyama
authors: Institute for Virus Research, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors: Ryoichiro
authors: R
authors: Kageyama
authors: Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors: Shinji
authors: S
authors: Uemoto
authors: Department of Clinical Application, Center for iPS cell Research and Application, Kyoto University, Kyoto, Japan.
authors: Yoshiya
authors: Y
authors: Kawaguchi
mesh_terms: D000367:Age Factors; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D000066670:Cell Plasticity; D018628:Gene Dosage; D015870:Gene Expression; D018398:Homeodomain Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D010183:Pancreatic Ducts / Q000166:cytology* / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*; D055758:SOX9 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D000072056:Transcription Factor HES-1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D051880:Receptors, Notch; D055758:SOX9 Transcription Factor; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; C489734:Hes1 protein, mouse; C062602:transcription factor PTF1