Development of 3-dimensional regeneration technique using salivary gland

• Project/Area Number: 15H02575
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Surgical dentistry
• Research Institution: Osaka University
• Principal Investigator: Sakai Takayoshi 大阪大学, 歯学研究科, 教授 (90379082)
• Co-Investigator(Kenkyū-buntansha): 野原 幹司 大阪大学, 歯学研究科, 准教授 (20346167) ; 福本 敏 東北大学, 歯学研究科, 教授 (30264253)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥41,210,000 (Direct Cost: ¥31,700,000、Indirect Cost: ¥9,510,000); Fiscal Year 2017: ¥11,960,000 (Direct Cost: ¥9,200,000、Indirect Cost: ¥2,760,000); Fiscal Year 2016: ¥15,990,000 (Direct Cost: ¥12,300,000、Indirect Cost: ¥3,690,000); Fiscal Year 2015: ¥13,260,000 (Direct Cost: ¥10,200,000、Indirect Cost: ¥3,060,000)
• Keywords: 唾液腺

Outline of Final Research Achievements

We identified the gene expression of salivary gland epithelium from our T7-SAGE library to regenerate salivary gland. Lactoferrin receptor 1 (LFR1) is one of genes that highly expresses in bud epithelium of salivary gland. Radiotherapy is commonly used in patients with head and neck cancer, and usually results in irreversible salivary glands damage and hypofunction. It is therefore important to manage such irradiation to prevent damage to the salivary glands. We investigated the radioprotective and regenerative effect of LF using both ex vivo submandibular salivary gland organ culture and ICR male mice in vivo. We found that LF had effects on both cell proliferation and CyclinD1-mediated cell-cycle progression which were regulated via the ERK1/2 and AKT signal transduction pathways. In addition, LF affected acinar cell structure and function after irradiation. These findings suggest that LF may be a useful agent to prevent irradiation effects in salivary glands.

Academic Significance and Societal Importance of the Research Achievements

放射線治療は外科的治療と同様に頭頸部癌に対して有効な治療法の１つであるが、照射領域に唾液腺が含まれると障害が生じる。障害が生じると治療を進めることが困難になる。唾液腺の放射線障害抑制と臓器再生を目指して、唾液腺上皮に発現する遺伝子ライブラリーを作製し、その中からLactoferrin (LF) receptor 1を見出した。LFを投与した唾液腺は、腺房細胞の構造と唾液分泌機能を維持していた。LFは唾液腺の放射線照射に対する防護作用を有しており、放射線障害に対する有用な薬剤であることが示唆された。本研究によって３次元的な再生治療薬の開発へと臨床応用が期待されている。

Research Products

• [Journal Article] The central clock controls the daily rhythm of Aqp5 expression in salivary glands. (2018)
  • Author(s): Uchida H, Nakamura TJ, Takasu NN, Obana-Koshino A, Ono H, Todo T, Sakai T, Nakamura W
  • Journal Title: J Physiol Sci. Volume: 68 Issue: 4 Pages: 377-385
  • DOI: 10.1007/s12576-017-0540-1
  • NAID: 40021574351
  • Peer Reviewed
• [Journal Article] Predictors of Side Effects With Long-Term Oral Appliance Therapy for Obstructive Sleep Apnea (2018)
  • Author(s): Minagi Hitomi Ono、Okuno Kentaro、Nohara Kanji、Sakai Takayoshi
  • Journal Title: J Clin Sleep Med Volume: 14 Issue: 01 Pages: 119-125
  • DOI: 10.5664/jcsm.6896
  • Peer Reviewed
• [Journal Article] Nuclear expression of claudin-3 in human colorectal adenocarcinoma cell lines and tissue (2018)
  • Author(s): Yasunori Tokuhara, Tatsuya Morinishi, Toru Matsunaga, Manabu Sakai, Takayoshi Sakai, Hiroyuki Ohsaki, Kyuichi Kadota, Yoshio Kushida, Reiji Haba, Eiichiro Hirakawa
  • Journal Title: Oncology letters Volume: 15 Pages: 99-108
  • DOI: 10.3892/ol.2017.7281
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dental and skeletal changes associated with long-term oral appliance use for obstructive sleep apnea: A systematic review and meta-analysis (2018)
  • Author(s): Araie Takafumi、Okuno Kentaro、Minagi Hitomi Ono、Sakai Takayoshi
  • Journal Title: Sleep Med Rev Volume: in press Pages: 161-172
  • DOI: 10.1016/j.smrv.2018.02.006
  • Peer Reviewed
• [Journal Article] Benefits of long-term pilocarpine due to increased muscarinic acetylcholine receptor 3 in salivary glands. (2018)
  • Author(s): Minagi HO, Ikai K, Araie T, Sakai M, Sakai T
  • Journal Title: Biochem Biophys Res Commun. Volume: 503 Issue: 2 Pages: 1098-1102
  • DOI: 10.1016/j.bbrc.2018.06.125
  • Peer Reviewed / Open Access
• [Journal Article] Runx1-Stat3 signaling regulates the epithelial stem cells in continuously growing incisors (2018)
  • Author(s): Sarper Safiye E.、Inubushi Toshihiro、Kurosaka Hiroshi、Ono Minagi Hitomi、Kuremoto Koh-ichi、Sakai Takayoshi、Taniuchi Ichiro、Yamashiro Takashi
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 29317-6
  • DOI: 10.1038/s41598-018-29317-6
  • Peer Reviewed / Open Access
• [Journal Article] Runx1-Stat3-Tgfb3 signaling network regulating the anterior palatal development (2018)
  • Author(s): Sarper Safiye E.、Kurosaka Hiroshi、Inubushi Toshihiro、Ono Minagi Hitomi、Kuremoto Koh-ichi、Sakai Takayoshi、Taniuchi Ichiro、Yamashiro Takashi
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 29681-3
  • DOI: 10.1038/s41598-018-29681-3
  • Peer Reviewed / Open Access
• [Journal Article] Grhl2 regulation of SPINT1 expression controls salivary gland development. (2018)
  • Author(s): Matsushita T, Sakai M, Yoshida H, Morita S, Hieda Y, Sakai T
  • Journal Title: Biochem Biophys Res Commun. Volume: 504 Issue: 1 Pages: 263-269
  • DOI: 10.1016/j.bbrc.2018.08.166
  • Peer Reviewed
• [Journal Article] The efficacy of nasal airway stent (Nastent) on obstructive sleep apnoea and prediction of treatment outcomes. (2018)
  • Author(s): Okuno K, Ono Minagi H, Ikai K, Matsumura Ai E, Takai E, Fukatsu H, Uchida Y, Sakai T
  • Journal Title: J Oral Rehabil. Volume: 46 Issue: 1 Pages: 51-57
  • DOI: 10.1111/joor.12725
  • Peer Reviewed
• [Journal Article] Generation of orthotopically functional salivary gland from embryonic stem cells (2018)
  • Author(s): Tanaka Junichi、Ogawa Miho、Hojo Hironori、Kawashima Yusuke、Mabuchi Yo、Hata Kenji、Nakamura Shiro、Yasuhara Rika、Takamatsu Koki、Irie Tarou、Fukada Toshiyuki、Sakai Takayoshi、Inoue Tomio、Nishimura Riko、Ohara Osamu、Saito Ichiro、Ohba Shinsuke、Tsuji Takashi、Mishima Kenji
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 4216-4216
  • DOI: 10.1038/s41467-018-06469-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sleep Stage Coordination Respiration and Swallowing: A Preliminary Study (2016)
  • Author(s): Okuno K, Nohara K, Takai E, Sakai T, Fleetham JA, Najib TA, Lowe AA, Ryan CF, Almeida FR
  • Journal Title: Dysphagia Volume: 31 Issue: 4 Pages: 579-586
  • DOI: 10.1007/s00455-016-9719-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Endoscopy evaluation to predict oral appliance outcomes in obstructive sleep apnea (2016)
  • Author(s): Okuno K, Sasao Y, Nohara K, Sakai T, Pliska BT, Lowe AA, Ryan CF, Almeida FR
  • Journal Title: European Respiratory Journal Volume: - Issue: 5 Pages: 1410-1419
  • DOI: 10.1183/13993003.01088-2015
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cryptochrome-dependent circadian periods in the arcuate nucleus. (2016)
  • Author(s): Uchida H, Nakamura TJ, Takasu NN, Todo T, Sakai T, Nakamura W.
  • Journal Title: Neurosci Lett. Volume: 610 Pages: 123-128
  • DOI: 10.1016/j.neulet.2015.10.071
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Regenerating Salivary Glands in the Microenvironment of Induced Pluripotent Stem Cells. (2015)
  • Author(s): Ono H, Obana A, Usami Y, Sakai M, Nohara K, Egusa H, Sakai T
  • Journal Title: Biomed Res Int. Volume: 2015 Pages: 293570-293570
  • DOI: 10.1155/2015/293570
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Peptide-modified Substrate for Modulating Gland Tissue Growth and Morphology In Vitro (2015)
  • Author(s): Taketa H, Sathi GA, Farahat M, Rahman KA, Sakai T, Hirano Y, Kuboki T, Torii Y, Matsumoto T
  • Journal Title: Sci Rep Volume: 5 Issue: 1 Pages: 11468-11468
  • DOI: 10.1038/srep11468
  • NAID: 120005697272
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Runx/Cbfb signaling regulates postnatal development of granular convoluted tubule in the mouse submandibular gland. (2015)
  • Author(s): Islam MN, Itoh S, Yanagita T, Sumiyoshi K, Hayano S, Kuremoto K, Kurosaka H, Honjo T, Kawanabe N, Kamioka H, Sakai T, Ishimaru N, Taniuchi I, Yamashiro T
  • Journal Title: Dev Dyn. Volume: 244(3) Issue: 3 Pages: 488-496
  • DOI: 10.1002/dvdy.24231
  • Peer Reviewed / Open Access
• [Presentation] Speech outcome of consecutive patients with UCLP (2016)
  • Author(s): Sugiyama C, Nozaki K, Nohara K, Hishikawa A, Ichikawa H, Tanaka N,Takai E, Sakai T
  • Organizer: The 11th congress of the Asian Pacific Craniofacial Association
  • Int'l Joint Research / Invited
• [Presentation] Development of The Videoendoscopic Evaluation of Saliva Aspiration (2016)
  • Author(s): Nohara K, Matsuno K, Sakai T
  • Organizer: The 6th ESSD Congress
  • Int'l Joint Research
• [Presentation] The role of RunX1 in salivary gland development (2016)
  • Author(s): Ono H, Safeye S, Kurosaka H, Sakai T, Yamashiro T
  • Organizer: International Symposium Oral and Craniofacial Development and Diseases 2016
  • Int'l Joint Research
• [Presentation] Models of salivary gland differentiation using induced pluripotent stem (iPS) cells. (2015)
  • Author(s): Ono H, Obana A, Usami Y, Sakai M, Miura J, Egusa H, Sakai T
  • Organizer: 47th Meeting of Continental European Division of the International Association for Dental Research
  • Place of Presentation: Antalya, Turkey
  • Year and Date: 2015-10-15
  • Int'l Joint Research