Production of human induced bronchiolar progenitors

2017 Fiscal Year Annual Research Report

• Project/Area Number: 15K15316
• Research Institution: Niigata University
• Principal Investigator: 菊地 利明 新潟大学, 医歯学系, 教授 (10280926)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 前駆細胞

Outline of Annual Research Achievements

細気管支前駆細胞（bronchiolar progenitor、以下「BP細胞」）は、細気管支上皮細胞への多分化能と自己複製能を有し、細気管支上皮の恒常性を維持している。われわれは最近、マウスでの予備実験の結果から、「分化した細気管支上皮細胞から、in vitroでBP細胞への脱分化を誘導する」ことを着想し、誘導性細気管支前駆細胞（induced BP、以下「iBP細胞」）の創製を提案するに至った。本研究ではまず、マウスiBP細胞への脱分化誘導法を確立し、その知見を応用することにより、ヒトiBP細胞の樹立を目指す。本研究の成果は、気道上皮細胞に特異的な脱分化機構の解明につながるだけでなく、再生医療に不可欠な生体材料を提供することで、革新的な医療技術の開発にも寄与する。研究初年度に当たる平成27年度は、iBP細胞の誘導をマウス体内で試み、さらに、誘導された細気管支前駆細胞の形質特性として、抗炎症効果を明らかにした。続く平成28年度は、in vitro培養実験を繰り返し、マウスiBP細胞の形質特性の解析を進めた。その結果、細気管支上皮細胞からiBP細胞への脱分化を誘導するのに最適な条件を明らかにすることができた。さらに平成29年度は、iBP細胞への脱分化を誘導する分子機構に、酸化ストレス応答のKeap1-Nrf2システムをどのように関わっていることを明らかにした。Nrf2は、プロテオグリカンのシンデカン4によって、Keap1との結合によるプロテオソーム分解から逃れて酸化ストレス防御遺伝子の転写を活性化するようになり、iBP細胞への脱分化を誘導していた。

Research Products

• [Journal Article] Peripheral alveolar nitric oxide concentration reflects alveolar inflammation in autoimmune pulmonary alveolar proteinosis. (2018)
  • Author(s): Hirano T, Ohkouchi S, Tode N, Kobayashi M, Ono M, Satoh T, Mitsuishi Y, Watanabe A, Tabata M, Irokawa T, Ogawa H, Sugiura H, Kikuchi T, Akasaka K, Tazawa R, Inoue Y, Nakata K, Kurosawa H, Ichinose M.
  • Journal Title: ERJ Open Res. Volume: 4 Pages: 00071-2017
  • DOI: 10.1183/23120541.00071-2017.
  • Peer Reviewed / Open Access
• [Journal Article] In vitro activity of various antibiotics against clinical strains of Legionella species isolated in Japan. (2018)
  • Author(s): Miyashita N, Kobayashi I, Higa F, Aoki Y, Kikuchi T, Seki M, Tateda K, Maki N, Uchino K, Ogasawara K, Kurachi S, Ishikawa T, Ishimura Y, Kanesaka I, Kiyota H, Watanabe A.
  • Journal Title: J Infect Chemother. Volume: 24 Pages: 325-329
  • DOI: 10.1016/j.jiac.2018.01.018.
  • Peer Reviewed / Open Access
• [Journal Article] Clinical significance of interferon-γ neutralizing autoantibodies against disseminated nontuberculous mycobacterial disease. (2018)
  • Author(s): Aoki A, Sakagami T, Yoshizawa K, Shima K, Toyama M, Tanabe Y, Moro H, Aoki N, Watanabe S, Koya T, Hasegawa T, Morimoto K, Kurashima A, Hoshino Y, Trapnell BC, Kikuchi T.
  • Journal Title: Clin Infect Dis. Volume: 66 Pages: 1239-1245
  • DOI: 10.1093/cid/cix996.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Endobronchial topical amphotericin B instillation for pulmonary chromomycosis after lung transplantation: A case report. (2018)
  • Author(s): Mitomo H, Sakurada A, Matsuda Y, Notsuda H, Watanabe T, Oishi H, Niikawa H, Maeda S, Noda M, Sado T, Amemiya T, Yoshida Y, Kikuchi T, Kamei K, Okada Y.
  • Journal Title: Transplant Proc. Volume: 50 Pages: 939-942
  • DOI: 10.1016/j.transproceed.2017.12.028.
  • Peer Reviewed / Open Access
• [Journal Article] A cluster analysis of bronchial asthma patients with depressive symptoms. (2018)
  • Author(s): Seino Y, Hasegawa T, Koya T, Sakagami T, Mashima I, Shimizu N, Muramatsu Y, Muramatsu K, Suzuki E, Kikuchi T.
  • Journal Title: Intern Med. Volume: 印刷中 Pages: 印刷中
  • DOI: 10.2169/internalmedicine.9073-17.
  • Peer Reviewed / Open Access
• [Journal Article] Clinical and genetic implications of mutation burden in squamous cell carcinoma of the lung. (2018)
  • Author(s): Okamoto T, Takada K, Sato S, Toyokawa G, Tagawa T, Shoji F, Nakanishi R, Oki E, Koike T, Nagahashi M, Ichikawa H, Shimada Y, Watanabe S, Kikuchi T, Akazawa K, Lyle S, Takabe K, Okuda S, Sugio K, Wakai T, Tsuchida M, Maehara Y.
  • Journal Title: Ann Surg Oncol. Volume: 25 Pages: 1564-1571
  • DOI: 10.1245/s10434-018-6401-1.
  • Peer Reviewed / Open Access
• [Journal Article] Natural course and potential prognostic factors for sleep-disordered breathing in multiple system atrophy. (2017)
  • Author(s): Ohshima Y, Nakayama H, Matsuyama N, Hokari S, Sakagami T, Sato T, Koya T, Takahashi T, Kikuchi T, Nishizawa M, Shimohata T.
  • Journal Title: Sleep Med. Volume: 34 Pages: 13-17
  • DOI: 10.1016/j.sleep.2017.01.020.
  • Peer Reviewed / Open Access
• [Journal Article] Megalin blockade with cilastatin suppresses drug-induced nephrotoxicity. (2017)
  • Author(s): Hori Y, Aoki N, Kuwahara S, Hosojima M, Kaseda R, Goto S, Iida T, De S, Kabasawa H, Kaneko R, Aoki H, Tanabe Y, Kagamu H, Narita I, Kikuchi T, Saito A.
  • Journal Title: J Am Soc Nephrol. Volume: 28 Pages: 1783-1791
  • DOI: 10.1681/ASN.2016060606.
  • Peer Reviewed / Open Access
• [Journal Article] Exome sequencing deciphers a germline MET mutation in familial epidermal growth factor receptor-mutant lung cancer. (2017)
  • Author(s): Tode N, Kikuchi T, Sakakibara T, Hirano T, Inoue A, Ohkouchi S, Tamada T, Okazaki T, Koarai A, Sugiura H, Niihori T, Aoki Y, Nakayama K, Matsumoto K, Matsubara Y, Yamamoto M, Watanabe A, Nukiwa T, Ichinose M.
  • Journal Title: Cancer Sci. Volume: 108 Pages: 1263-1270
  • DOI: 10.1111/cas.13233.
  • Peer Reviewed / Open Access
• [Journal Article] A-DROP system for prognostication of NHCAP inpatients. (2017)
  • Author(s): Koizumi T, Tsukada H, Ito K, Shibata S, Hokari S, Tetsuka T, Aoki N, Moro H, Tanabe Y, Kikuchi T.
  • Journal Title: J Infect Chemother. Volume: 23 Pages: 523-530
  • DOI: 10.1016/j.jiac.2017.04.013.
  • Peer Reviewed / Open Access
• [Journal Article] Transfer of in vitro-expanded naïve T cells after lymphodepletion enhances antitumor immunity through the induction of polyclonal antitumor effector T cells. (2017)
  • Author(s): Tanaka T, Watanabe S, Takahashi M, Sato K, Saida Y, Baba J, Arita M, Sato M, Ohtsubo A, Shoji S, Nozaki K, Ichikawa K, Kondo R, Aoki N, Ohshima Y, Sakagami T, Abe T, Moro H, Koya T, Tanaka J, Kagamu H, Yoshizawa H, Kikuchi T.
  • Journal Title: PLoS One. Volume: 12 Pages: e0183976
  • DOI: 10.1371/journal.pone.0183976.
  • Peer Reviewed / Open Access
• [Journal Article] Phenotypic analysis of asthma in Japanese athletes. (2017)
  • Author(s): Tsukioka K, Koya T, Ueno H, Hayashi M, Sakagami T, Hasegawa T, Arakawa M, Suzuki E, Kikuchi T.
  • Journal Title: Allergol Int. Volume: 66 Pages: 550-556
  • DOI: 10.1016/j.alit.2017.02.009.
  • Peer Reviewed / Open Access
• [Journal Article] Clinical presentation of Legionella pneumonia: Evaluation of clinical scoring systems and therapeutic efficacy. (2017)
  • Author(s): Miyashita N, Higa F, Aoki Y, Kikuchi T, Seki M, Tateda K, Maki N, Uchino K, Ogasawara K, Kiyota H, Watanabe A.
  • Journal Title: J Infect Chemother. Volume: 23 Pages: 727-732
  • DOI: 10.1016/j.jiac.2017.09.001.
  • Peer Reviewed / Open Access
• [Journal Article] Effect of lymphodepletion on donor T cells and the role of recipient cells persisting after cytotoxic treatments in cancer Immunotherapies. (2017)
  • Author(s): Watanabe S, Arita M, Takahashi M, Saida Y, Koya T, Kikuchi T.
  • Journal Title: Crit Rev Immunol. Volume: 37 Pages: 59-73
  • DOI: 10.1615/CritRevImmunol.2018019497.
  • Peer Reviewed / Open Access
• [Presentation] ゲノム医学からみた肺感染症 (2017)
  • Author(s): 菊地利明
  • Organizer: 第57回日本呼吸器学会学術講演会
  • Invited
• [Presentation] Autoimmune Nontuberculous Mycobacterial Disease:Characteristic Phenotypes of Cases with Anti-Interferon-g Neutralizing Autoantibodies. (2017)
  • Author(s): A. Aoki, T. Sakagami, K. Yoshizawa, K. Shima, N. Aoki, H. Moro, Y. Tanabe, T. Koya, T. Hasegawa, T. Kikuchi.
  • Organizer: 2017 American Thoracic Society International Conference
  • Int'l Joint Research
• [Presentation] The Risk of Exacerbation for Asthma from Questionnaire Survey in Japanese Population. (2017)
  • Author(s): H. Ueno, T. Koya, K. Yoshizawa, A. Aoki, Y. Kimura, H. Takeuchi, M. Hayashi, T. Sakagami, T. Kikuchi, T. Hasegawa, E. Suzuki.
  • Organizer: 2017 American Thoracic Society International Conference
  • Int'l Joint Research
• [Presentation] Comparison Between Ventilator-Associated Events and Conventional Ventilator Associated Pneumonia Surveillance in Japan. (2017)
  • Author(s): M. Sato, Y. Tanabe, M. Uchiyama, A. Sakagami, C. Tsubata, H. Cho, N. Aoki, H. Moro, H. Endoh, T. Kikuchi, A. Saitoh.
  • Organizer: 2017 American Thoracic Society International Conference
  • Int'l Joint Research
• [Presentation] Establishment of a Web-Based Inquiry System for Elemental Analysis of Lung Tissue of Occupational Lung Diseases. (2017)
  • Author(s): H. Moriyama, M. Kobayashi, A. Aoki, K. Asakawa, T. Sakagami, T. Koya, T. Ohdaira, T. Takada, T. Kikuchi.
  • Organizer: 2017 American Thoracic Society International Conference
  • Int'l Joint Research
• [Presentation] Anti-BPIFB1 Autoantibodies Were Identified in Three Cases with Idiopathic Interstitial Lung Disease. (2017)
  • Author(s): K. Yoshizawa, T. Sakagami, A. Aoki, K. Asakawa, T. Koya, T. Takada, T. Kikuchi.
  • Organizer: 2017 American Thoracic Society International Conference
  • Int'l Joint Research
• [Presentation] Involvement of Extracellular ATP in Mucus Production During Rhinovirus Infection. (2017)
  • Author(s): H. Aizawa, A. Koarai, Y. Shishikura, M. Yamaya, H. Sugiura, M. Watanabe, Y. Hashimoto, T. Numakura, T. Makiguchi, K. Abe, M. Yamada, T. Kikuchi, Y. Hoshikawa, Y. Okada, M. Ichinose.
  • Organizer: 2017 American Thoracic Society International Conference
  • Int'l Joint Research
• [Presentation] Mycophenolate Mofetil for Japanese Patients with Interstitial Lung Diseases in Amyopathic Dermatomyositis with Anti-MDA-5 Antibody. (2017)
  • Author(s): T. Takada, K. Asakawa, A. Aoki, M. Hayashi, T. Sakagami, T. Kikuchi.
  • Organizer: 2017 American Thoracic Society International Conference
  • Int'l Joint Research
• [Book] Lung Disease Associated with Rheumatioid Arthritis. (2018)
  • Author(s): Moro H, Kikuchi T.
  • Total Pages: 199
  • Publisher: Springer Nature Singapore Pte
  • ISBN: 978-981-10-6749-5
• [Book] 診療ガイドライン UP-TO-DATE 2018-2019 (2017)
  • Author(s): 茂呂寛、菊地利明
  • Total Pages: 1037
  • Publisher: メディカルレビュー社
  • ISBN: 978-4-7792-2008-1
• [Remarks] 新潟大学大学院医歯学総合研究科 呼吸器・感染症内科学分野
  • URL: http://www.med.niigata-u.ac.jp/resp/welcome.html