Human alveolar epithelial progenitor cells revealed pathophysiological mechanisms of refractory pulmonary diseases

2012 Fiscal Year Final Research Report

• Project/Area Number: 22390163
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Tohoku University
• Principal Investigator: KUBO Hiroshi 東北大学, 大学院・医学系研究科, 准教授 (20332504)
• Co-Investigator(Kenkyū-buntansha): KATO Hidemasa 埼玉医科大学, 医学部, 講師 (50292123)
• Project Period (FY): 2010 – 2012
• Keywords: 組織幹細胞 / 肺胞 II 型上皮細胞 / COPD / 肺線維症 / 遺伝子発現 / 細胞治療 / 再生 医療 / 呼吸器病学

Research Abstract

We developed a novel technique of cell isolation from human lung tissue, using a combination of cell surface antigens. This novel method enables the isolation of different cellular components from normal and diseased lungs, and is capable of elucidating phenotypes specific to certain alveolar cell types indicative of lung disease. Then, we identified genes commonly or differentially expressed by alveolar type II (ATII)-like cells differentiated from progenitor cells and mature ATII cells isolated from human lung tissues. Furthermore, we compared the genes expressed in ATII cells obtained from chronic obstructive pulmonary disease (COPD) and non-COPD patients, and found that interferon-stimulated genes associated with antigen processing and presentation were enriched in COPD-ATII cells. Genes involved in cell cycle progression were upregulated in COPD-ATII cells and the number of ATII cells in COPD lungs were increased. We also found that ATII cells isolated from patients with pulmonary fibrosis demonstrated increased severity of 2009 pandemic influenza A virus infection. This cell-based pulmonology will open a new strategy to treat intractable pulmonary diseases.

Research Products

• [Journal Article] Increased severity of H1N1 pandemic influenza virus infection in alveolar type II cells from patients with pulmonary fibrosis (2013)
  • Author(s): Fujino N, Kubo H, Ota C, Suzuki T, Takahashi T, Yamada M, Suzuki S, Kondo T, Nagatomi R, Tando Y, Yamaya M.
  • Journal Title: J Infect Dis Volume: 207 Pages: 692-693
  • DOI: doi:10.1093/infdis/jis739
  • Peer Reviewed
• [Journal Article] Differences in the released endothelial microparticle subtypes between humanpulmonary microvascular endothelial cells and aortic endothelial cells in vitro (2013)
  • Author(s): Takahashi T, Kobayashi S, Fujino N, Suzuki T, Ota C, Tando Y, He M, Yamada M, Kurosawa S, Yamaya M, Kubo H
  • Journal Title: Exp Lung Res Volume: 39 Pages: 155-161
  • DOI: doi:10.3109/01902148.2013.784932
  • Peer Reviewed
• [Journal Article] Gene expression profiles of alveolar type II cells of chronic obstructive pulmonary disease: A case-control study (2012)
  • Author(s): Fujino N, Ota C, Takahashi T, Suzuki T, Suzuki S, Yamada M, Nagatomi R, Kondo T, Yamaya M, Kubo H
  • Journal Title: BMJ Open Volume: 2 Pages: e001553
  • DOI: doi:10.1136/bmjopen-2012-001553
  • Peer Reviewed
• [Journal Article] Analysis of gene expression profiles inalveolar epithelial type II-like cells differentiated from human alveolar epithelial progenitor cells (2012)
  • Author(s): Fujino N, Ota C, Suzuki T, Suzuki S, Hegab AE, Yamada M, Takahashi T, He M, Kondo T, Kato H, Yamaya M, Kubo H.
  • Journal Title: Respir Invest Volume: 50 Pages: 110-116
  • DOI: doi:10.1016/j.resinv.2012.07.002
  • Peer Reviewed
• [Journal Article] A novel method for isolating individual cellular components from the adult human distal lung (2012)
  • Author(s): Fujino N, Kubo H, Ota C, Suzuki T, Suzuki S, Yamada M, Takahashi T, He M, Suzuki T, Kondo T, Yamaya M.
  • Journal Title: Am J Respir Cell Mol Biol Volume: 46 Pages: 422-430
  • DOI: doi:10.1165/rcmb.2011-0172OC
  • Peer Reviewed
• [Journal Article] Clinical prospects for treating COPD with regenerative approaches (2012)
  • Author(s): Kubo H.
  • Journal Title: Stem Cells Trans Med Volume: 1 Pages: 627-631
  • Peer Reviewed
• [Journal Article] Tissue engineering for pulmonary diseases - Insights from the laboratory (2012)
  • Author(s): Kubo H.
  • Journal Title: Respirology Volume: 17 Pages: 445-454
  • DOI: DOI:10.5966/sctm.2012-0065
  • Peer Reviewed
• [Journal Article] Increased circulating endothelial microparticles in COPD patients: a potential biomarker for COPD exacerbation susceptibility (2012)
  • Author(s): Takahashi T, Kobayashi S, Fujino N, Suzuki T, Ota C, He M, Yamada M, Suzuki S, Yanai M, Kurosawa S, Yamaya M, Kubo H.
  • Journal Title: Thorax Volume: 67 Pages: 1067-1074
  • DOI: doi:10.1136/thoraxjnl-2011-201395
  • Peer Reviewed
• [Journal Article] L-carbocisteine inhibits respiratory syncytial virus infection in human tracheal epithelial cells (2012)
  • Author(s): Asada M, Yoshida M, Hatachi Y, Sasaki T, Yasuda H, Deng X, Nishimura H, Kubo H, Nagatomi R, Yamaya M.
  • Journal Title: Respir Physiol Neurobiol Volume: 180 Pages: 112-118
  • DOI: doi:10.1016/j.resp.2011.10.017
  • Peer Reviewed
• [Journal Article] Administration of a specific inhibitor of neutrophil elastase attenuates pulmonary fibrosis after acute lung injury in mice (2012)
  • Author(s): Fujino N, Kubo H, Suzuki T, He M, Suzuki T, Yamada M, Takahashi T, Ota C, Yamaya M.
  • Journal Title: Exp Lung Res Volume: 38 Pages: 28-36
  • DOI: doi:10.3109/01902148.2011.633306
  • Peer Reviewed
• [Journal Article] p62/SQSTM1Accumulation is associated with poor prognosis of lung adenocarcinomapatients (2012)
  • Author(s): Inoue D, Suzuki T, Mitsuishi Y, Miki Y, Suzuki S, Sugawara S, Watanabe M, Sakurada A, Endo C, Uruno A, Sasano H, Nakagawa T, Satoh K, Tanaka N, Kubo H, Motohashi H, Yamamoto M.
  • Journal Title: Cancer Science Volume: 103 Pages: 760-766
  • DOI: doi:10.1111/j.1349-7006.2012.02216.x
  • Peer Reviewed
• [Journal Article] Repetetive pneumonia and wheezing in an elderly patient after radiation therapy (2012)
  • Author(s): Yoshida M, Yamaya M, Asada M, Kubo H, Arai H.
  • Journal Title: Geriatr Gerontol Int Volume: 12 Pages: 352-353
  • DOI: doi:10.1111/j.1447-0594.2011.00751.x
  • Peer Reviewed
• [Journal Article] Surgical stress increases circulating endothelial microparticlesin the elderly (2012)
  • Author(s): Takahashi T, Kubo H, Fujino N, Suzuki T, Ota C, Yamada M, Yamaya M, Suzuki S, Kurosawa S.
  • Journal Title: Anaesthesia & Intensive Care Volume: 40 Pages: 899-902
  • URL: http://www.aaic.net.au/document/?D=20120405
  • Peer Reviewed
• [Journal Article] Inhibitory effects of tiotropium on rhinovirus infection in human airway epithelial cells (2012)
  • Author(s): Yamaya M, Nishimura H, Hatachi Y, Yasuda H, Deng X, Sasaki T, Kubo H, and Nagatomi R
  • Journal Title: Eur Respir J Volume: 40 Pages: 122-132
  • Peer Reviewed
• [Journal Article] Levofloxacin inhibits rhinovirus infection in primary cultures of human tracheal epithelial cells (2012)
  • Author(s): Yamaya M, Nishimura H, Hatachi Y, Yasuda H, Deng X, Sasaki T, Mizuta K, Kubo H, and Nagatomi R.
  • Journal Title: Antimicrob Agents Chemother Volume: 56 Pages: 4052-4061
  • DOI: doi:10.1128/AAC.00259-12
  • Peer Reviewed
• [Journal Article] Isolation of alveolar epithelial type II progenitor cells from adult human lungs (2011)
  • Author(s): Fujino N, Kubo H, Suzuki T, Ota C, Hegab AE, He M, Suzuki S, Suzuki T, Yamada M, Kondo T, Kato H, Yamaya M.
  • Journal Title: Lab Invest Volume: 91 Pages: 363-378
  • DOI: doi:10.1038/labinvest.2010.187
  • Peer Reviewed
• [Journal Article] Procaterol inhibits rhinovirus infection in primary cultures of human tracheal epithelial cells (2011)
  • Author(s): Yamaya M, Nishimura H, Hatachi Y, Yoshida M, Fujiwara H, Asada M, Nakayama K, Yasuds H, Deng X, Sasaki T, Kubo H, and Nagatomi R
  • Journal Title: Eur J Pharmacol Volume: 650 Pages: 431-444
  • DOI: doi:10.1016/j.ejphar.2010.09.056
  • Peer Reviewed
• [Journal Article] Molecular Basis of Lung Tissue Regeneration (2011)
  • Author(s): Kubo H.
  • Journal Title: Gen Thorac Cardiovasc Surg Volume: 59 Pages: 231-244
  • DOI: doi:10.1007/s11748-010-0757-x
  • Peer Reviewed
• [Journal Article] Inducible disruption of autophagy in the lung causes airwayhyper-responsiveness (2011)
  • Author(s): Inoue D, Kubo H, Taguchi K, Suzuki T, Komatsu M, Motohashi H and Yamamoto M.
  • Journal Title: Biochem BiophysRes Commun Volume: 405 Pages: 13-18
  • DOI: doi:10.1016/j.bbrc.2010.12.092
  • Peer Reviewed
• [Journal Article] Impaired endothelial progenitor cell mobilization and colony-forming capacity in chronic obstructive pulmonary disease (2011)
  • Author(s): Takahashi T, Suzuki S, Kubo H, Yamaya M, Kurosawa S, Kato M.
  • Journal Title: Respirology Volume: 16 Pages: 680-687
  • Peer Reviewed
• [Journal Article] RAGE binds phosphatidylserine and assists in the clearance of apoptotic cells (2011)
  • Author(s): He M, Kubo H, Morimoto K, Fujino N, Suzuki T, Takahashi T, Yamada M, Yamaya M, Maekawa T, Yamamoto Y, Yamamoto H.
  • Journal Title: EMBO Reports Volume: 12 Pages: 358-364
  • DOI: doi:10.1038/embor.2011.28
  • Peer Reviewed
• [Journal Article] The increase in surface CXCR4 expression on lung extravascular neutrophils and its effects on neutrophils during endotoxin-induced lung injury (2011)
  • Author(s): Yamada M, Kubo H, Kobayashi S, Ishizawa K, He M, Suzuki T, Fujino N, Kunishima H, Hatta M, Nishimaki K, Aoyagi T, Tokuda K, Kitagawa M, Yano H, Tamamura H, Fujii N, Kaku M.
  • Journal Title: Cell Mol Immunol Volume: 5 Pages: 305-314
  • DOI: doi:10.1038/cmi.2011.8
  • Peer Reviewed
• [Journal Article] Surfactant protein C G100S mutation causes familial pulmonary fibrosis in Japanese kindred (2011)
  • Author(s): Ono S, Tanaka T, Ishida M, Kinoshita A, Fukuoka J, Takaki M, Sakamoto N,Ishimatsu Y, Kohno S, Hayashi T, Senba M, Yasunami M, Kubo Y, Yoshida LM, Kubo H, Ariyoshi K, Yoshiura K, Morimoto K.
  • Journal Title: Eur Respir J Volume: 38 Pages: 861-869
  • DOI: doi:10.1183/09031936.00143610
  • Peer Reviewed
• [Journal Article] Evidence forHuman Lung Stem Cells (2011)
  • Author(s): Suzuki T, Kondo T, Kubo H.
  • Journal Title: New Engl J Med Volume: 365 Pages: 464-466
  • DOI: doi:10.1056/NEJMc1106693
  • Peer Reviewed
• [Presentation] International Symposium 4: Mechanisms of lung injury and repair. Lung injury and repair -the role of the receptor for advanced glycation end-products (RAGE) (2012)
  • Author(s): 久保裕司
  • Organizer: 第52回日本呼吸器学会学術講 演会
  • Place of Presentation: 神戸
  • Year and Date: 20120420-22
• [Presentation] 特別講演:肺胞の破 壊と再構築 -肺胞構成細胞の変化 (2012)
  • Author(s): 久保裕司
  • Organizer: 第21回 Kinki Chest Club
  • Place of Presentation: 大阪
  • Year and Date: 2012-10-27
• [Presentation] 特別講演:急性肺損傷における組織修復 (2012)
  • Author(s): 久保裕司
  • Organizer: 第22回日本集中治療医学会九州地方会
  • Place of Presentation: 鹿児島
  • Year and Date: 2012-07-14
• [Presentation] Number Of Circulating Endothelial Microparticles Are Increased During Acute Exacerbation Of COPD; Potential Biomarkers For Progression Of Exacerbation (2012)
  • Author(s): Takahashi T, Kobayashi S, Fujino N, Suzuki T, Ota C, Yamada M, He M, Kurosawa S, Yamaya M, and Kubo H.
  • Organizer: American Thoracic Society International Conference
  • Place of Presentation: サンフランシスコ,米国
  • Year and Date: 2012-05-21
• [Presentation] Gene Expression Profiles Of Alveolar Type II Cells From COPD Patients (2012)
  • Author(s): Fujino N, Ota C, Suzuki T, Suzuki S, Yamada M, Takahashi T, He M, Kondo T,Yamaya M, and Kubo H.
  • Organizer: American Thoracic Society International Conference
  • Place of Presentation: サン フランシスコ,米国
  • Year and Date: 2012-05-21
• [Presentation] Deacetylase Inhibitor Restores The Gene Expression Of Human Lung Surfactant Protein C DuringEpithelial-Mesenchymal Transition in vitro (2012)
  • Author(s): Ota C, Fujino N, Yamada M, Motohashi H, Kato H, Yamaya M, and Kubo H. Histone
  • Organizer: American Thoracic Society International Conference
  • Place of Presentation: サンフランシ スコ,米国
  • Year and Date: 2012-05-21
• [Presentation] Supplementation Of MiR-200c Or Inhibition Of MiR-21Attenuates TGF-ss-InducedEpithelial-Mesenchymal Transition In Mouse Alveolar Type II Cells (2012)
  • Author(s): Yamada M, Kubo H, Fujino N, Ota C, SuzukiT, Takahashi T, Kunishima H, Aoyagi T, Yamaya M, and Kaku M.
  • Organizer: American Thoracic Society International Conference
  • Place of Presentation: サンフランシスコ,米国
  • Year and Date: 2012-05-21
• [Presentation] Formoterol And Budesonide Inhibit Rhinovirus Infection In Human Airway Epithelial Cells (2012)
  • Author(s): Yamaya M, Hatachi Y, Kubo H, and Nishimura H.
  • Organizer: American Thoracic Society International Conference
  • Place of Presentation: サンフランシ スコ,米国
  • Year and Date: 2012-05-21
• [Presentation] Tulobuterol Inhibits Rhinovirus Infection In Human Airway Epithelial Cells (2012)
  • Author(s): Yamaya M, Hatachi Y, Kubo H, and Nishimura H.
  • Organizer: American Thoracic Society International Conference
  • Place of Presentation: サン フランシスコ,米国
  • Year and Date: 2012-05-21
• [Presentation] L-Carbocisteine InhibitsRespiratory Syncytial Virus Infection In Human Airway Epithelial Cells (2012)
  • Author(s): Yamaya M, Hatachi Y, Kubo H, andNishimura H.
  • Organizer: American Thoracic Society International Conference
  • Place of Presentation: サンフランシ スコ,米国
  • Year and Date: 2012-05-21
• [Presentation] 特別講演:呼吸器病学への再生医療の応用 (2012)
  • Author(s): 久保裕司
  • Organizer: 第2回長崎呼吸器疾患と移植再生フォーラム
  • Place of Presentation: 長崎
  • Year and Date: 2012-04-05
• [Presentation] 特別講演:急性肺損傷:修復のメカニズム (2012)
  • Author(s): 久保裕司
  • Organizer: 第11回福岡肺分子病態研究会
  • Place of Presentation: 福岡
  • Year and Date: 2012-01-08
• [Presentation] Endogenous progenitor cells in adult human lungs (2011)
  • Author(s): Kubo H, Fujino N, Suzuki T, Ota C, He M, Yamada M, Yamaya M.
  • Organizer: 15th Congress of the Asian Pacific Society of Respirology
  • Place of Presentation: マニラ,フィ リピン
  • Year and Date: 20111122-25
• [Presentation] Concurrent Symposia: Cell and Molecular Biology. Roles of Stem Cells in the Lung (2011)
  • Author(s): Kubo H
  • Organizer: The 16th Congress of the APSR
  • Place of Presentation: 上海,中国
  • Year and Date: 2011-11-06
• [Presentation] 特別講演:肺再生研究の現状 (2011)
  • Author(s): 久保裕司
  • Organizer: Respiratory Symposium in 札幌
  • Place of Presentation: 札幌
  • Year and Date: 2011-09-10
• [Presentation] 急性肺損傷-個別化医療・細胞治療の可能性 (2011)
  • Author(s): 久保裕司
  • Organizer: 第32回日本呼吸器学会生涯教育講演会
  • Place of Presentation: 東京
  • Year and Date: 2011-08-20
• [Presentation] 特別講演:肺再生医療について-これからの呼吸器病学 (2011)
  • Author(s): 久保裕司
  • Organizer: 第5回神奈川COPD先端治療研究会
  • Place of Presentation: 横浜
  • Year and Date: 2011-07-07
• [Presentation] 「細胞から見た呼吸器病学」の はじまり (2011)
  • Author(s): 久保裕司
  • Organizer: Meet the Specialist -呼吸器 疾患の診断と治療-
  • Place of Presentation: 東京
  • Year and Date: 2011-05-27
• [Presentation] A novel differentiation assay system for human alveolar epithelialtype ii cells from alveolar epithelial stem/progenitor cells in vitro (2011)
  • Author(s): Ota C, Fujino N, Suzuki T, He M, Suzuki S, Yamada M, Kondo T, Kato H, Yamaya M, Kubo H.
  • Organizer: American Thoracic Society International Conference
  • Place of Presentation: デンバー,米 国
  • Year and Date: 2011-05-18
• [Presentation] A newflow-cytometric method for isolating component cells individually from adult human distal lungs (2011)
  • Author(s): Fujino N, Ota C, Suzuki T, He M, Takahashi T, Yamada M, Suzuki S, Kondo T, Yamaya M, Kubo H.
  • Organizer: American Thoracic Society International Conference
  • Place of Presentation: デン バー,米国
  • Year and Date: 2011-05-18
• [Presentation] Expression patterns of two important regulatory microRNAs inepithelial-mesenchymal transition during experimental bleomycin-induced lung fibrosis (2011)
  • Author(s): Yamada M, Kubo H, Fujino N, He M, Suzuki T, Takahashi T, Ota C, Aoyagi T, Kunishima H, Yamaya M, Kaku M.
  • Organizer: American Thoracic Society International Conference
  • Place of Presentation: デン バー,米国
  • Year and Date: 2011-05-18
• [Presentation] Circulating endothelial microparticles are increased in patients with COPD; a potential novel biomarker for COPD (2011)
  • Author(s): Takahashi T, Suzuki S, Kobayashi S, HeM, Suzuki T, Fujino N, Ota C, Kurosawa S, Kato M, Yamaya M, Kubo H.
  • Organizer: American Thoracic Society International Conference
  • Place of Presentation: デンバー,米 国
  • Year and Date: 2011-05-18
• [Presentation] 特別講演:肺の損傷と修復-肺胞に幹細胞は存在するか? (2010)
  • Author(s): 久保裕司
  • Organizer: 第3回九州胸部疾患研究グループ(KREST-SG)の会
  • Place of Presentation: 大分
  • Year and Date: 2010-11-27
• [Presentation] 難治性肺疾患に対する肺再生・修復治療の開発をめざして (2010)
  • Author(s): 久保裕司
  • Organizer: 第12回東海分子呼吸器研究会
  • Place of Presentation: 名古屋
  • Year and Date: 2010-08-27
• [Book] 特集注目される呼吸器疾患の病態・診断・治療「急性肺傷害における肺胞上皮傷害と修復」呼吸器内科 (2013)
  • Author(s): 久保裕司
  • Total Pages: 25-31
  • Publisher: 科学評論社
• [Book] 一週一話:肺の再生医療-研究 の現状と今後の展望.日本医事新報 (2012)
  • Author(s): 久保裕司
  • Total Pages: 34-35
  • Publisher: 日本医事新報社
• [Book] 特集呼吸器のサイエンス「肺血管再生医療の現状」.アンチ・エイジング医学(日本抗加齢医学会雑誌) (2012)
  • Author(s): 久保裕司
  • Total Pages: 555-560
  • Publisher: メディカルレビュー社
• [Book] 総説 肺の stem cells.呼吸 (2012)
  • Author(s): 久保裕司
  • Total Pages: 1085-1092
  • Publisher: Respiration Research Foundation
• [Book] 呼吸と循環.炎症損傷における組織幹細胞 (2011)
  • Author(s): 久保裕司
  • Total Pages: 165-170
  • Publisher: 医学書院
• [Book] 特集急性肺損傷/急性呼吸窮迫症候群(ALI/ARDS):診断と治療の進歩.トピックスIV.最近の話題.3.急性肺損傷における細胞治療の可能性.日内会誌 (2011)
  • Author(s): 久保裕司
  • Total Pages: 1613-1618
  • Publisher: 日本内科学会
• [Book] 特集COPD-生命予後の改善を目指して-:COPDの治療.非薬物療法.肺再生医療の現状と今後の展望.日本臨牀 (2011)
  • Author(s): 久保裕司
  • Total Pages: 1869-1872
  • Publisher: 日本臨牀社
• [Book] 肺のprogenitor cellについて.呼吸 (2010)
  • Author(s): 久保裕司
  • Total Pages: 590-594
  • Publisher: 中外医学社
• [Book] 第80回閉塞性肺疾患研究会.「COPD 研究の最前線:基礎から臨床まで」 幹細胞より見た COPD:肺再生へのアプローチ.呼吸 (2010)
  • Author(s): 久保裕司
  • Total Pages: 744-747
  • Publisher: Respiration Research Foundation
• [Book] 別冊・医学のあゆみ最新ARDSのすべて再生医療・細胞治療の可能性 (2010)
  • Author(s): 久保裕司
  • Total Pages: 387-392
  • Publisher: 医歯薬出版株式会社
• [Book] 喘息/COPD の基礎研究最前線. COPD における組織幹細胞の関与International Review of Asthma & COPD (2010)
  • Author(s): 久保裕司
  • Total Pages: 21-26
  • Publisher: Medical Review社
• [Book] ARDS up-to-date:ARDS治療へ向けた幹細胞研究の進歩Shock (2010)
  • Author(s): 久保裕司
  • Total Pages: 18-23
  • Publisher: 日本ショック学会
• [Book] 炎症損傷における組織幹細胞の関与.日本アレルギー学会誌 (2010)
  • Author(s): 久保裕司
  • Total Pages: 667-70
  • Publisher: 日本アレルギー学会
• [Remarks]
  • URL: http://www.apmid.med.tohoku.ac.jp/