ALDH activity-guided detection of lung tissue stem cells and its therapeutic use for pulmonary fibrosis

• Project/Area Number: 17K09654
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Hiroshima University
• Principal Investigator: Nakashima Taku 広島大学, 病院(医), 助教 (90643792)
• Co-Investigator(Kenkyū-buntansha): 服部 登 広島大学, 医系科学研究科(医), 教授 (00283169)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 肺線維症 / 組織幹細胞 / ALDH / 間質性肺炎 / ブレオマイシン / 肺障害 / 細胞治療

Outline of Final Research Achievements

We have shown that the newly identified CD45-negative ALDH bright cells in the lung are reduced with the onset of murine pulmonary fibrosis in lung, and that they can be a novel tool for cell therapy to ameliorate pulmonary fibrosis and it's mortality when administered to the lung.
There was a strong association between the amount of lung CD45-negative ALDH bright cells and the extent of pulmonary fibrosis. Additionally, mice treated with CD45-negative ALDH bright cells showed suppress fibrosis by reducing inflammatory cytokines. This cell therapy could be a new treatment for pulmonary fibrosis, for which there is no effective treatment available to date.

Academic Significance and Societal Importance of the Research Achievements

肺線維症は、有効な治療法がなく生命予後の著しく不良な難治性疾患である。そのなかでも今日に至るまで原因が明らかとされていない特発性肺線維症については、その病態を解明するため多方面からの様々な取り組みがなされており、「肺組織幹細胞の機能不全」が肺線維症を悪化させるメカニズムの1つとして提唱されている。
本研究を通じて全く新たなアプローチで同定・採取されたマウス肺組織幹細胞であるCD45陰性ALDH高発現細胞による細胞治療は、現在に至るまで有効な治療法のないヒト肺線維症に対する新規細胞治療のツールへと発展が期待できる。

Research Products

• [Journal Article] Serum high-mobility group box 1 is associated with the onset and severity of acute exacerbation of idiopathic pulmonary fibrosis. (2020)
  • Author(s): Yamaguchi K, Iwamoto H, Sakamoto S, Horimasu Y, Masuda T, Miyamoto S, Nakashima T, Ohshimo S, Fujitaka K, Hamada H, Hattori N.
  • Journal Title: Respirology. Volume: 25 Issue: 3 Pages: 275-280
  • DOI: 10.1111/resp.13634
  • Peer Reviewed
• [Journal Article] Inhibition of PAI‐1 limits chemotherapy resistance in lung cancer through suppressing myofibroblast characteristics of cancer‐associated fibroblasts (2019)
  • Author(s): Masuda Takeshi、Nakashima Taku、Namba Masashi、Yamaguchi Kakuhiro、Sakamoto Shinjiro、Horimasu Yasushi、Miyamoto Shintaro、Iwamoto Hiroshi、Fujitaka Kazunori、Miyata Yoshihiro、Hamada Hironobu、Okada Morihito、Hattori Noboru
  • Journal Title: Journal of Cellular and Molecular Medicine Volume: 23 Issue: 4 Pages: 2984-2994
  • DOI: 10.1111/jcmm.14205
  • Peer Reviewed / Open Access
• [Journal Article] Suplatast tosilate reduces radiation-induced lung injury in mice through suppression of oxidative stress. (2019)
  • Author(s): Izumi Y, Nakashima T, Masuda T, Shioya S, Fukuhara K, Yamaguchi K, Sakamoto S, Horimasu Y, Miyamoto S, Iwamoto H, Fujitaka K, Hamada H, Hattori N.
  • Journal Title: Free Radic Biol Med. Volume: 136 Pages: 52-59
  • DOI: 10.1016/j.freeradbiomed.2019.03.024
  • Peer Reviewed
• [Journal Article] Role of B7H3/IL-33 Signaling in Pulmonary Fibrosis-induced Profibrogenic Alterations in Bone Marrow. (2019)
  • Author(s): Nakashima T, Liu T, Hu B, Wu Z, Ullenbruch M, Omori K, Ding L, Hattori N, Phan SH.
  • Journal Title: Am J Respir Crit Care Med. Volume: 200 Issue: 8 Pages: 1032-1044
  • DOI: 10.1164/rccm.201808-1560oc
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Comparison of anti-aminoacyl-tRNA synthetase antibody-related and idiopathic non-specific interstitial pneumonia. (2019)
  • Author(s): Shioya S, Masuda T, Yamaguchi K, Sakamoto S, Horimasu Y, Nakashima T, Miyamoto S, Senoo T, Iwamoto H, Ohshimo S, Fujitaka K, Hamada H, Hattori N.
  • Journal Title: Respir Med. Volume: 152 Pages: 44-50
  • DOI: 10.1016/j.rmed.2019.04.023
  • Peer Reviewed
• [Journal Article] Pre-existing interstitial lung abnormalities are risk factors for immune checkpoint inhibitor-induced interstitial lung disease in non-small cell lung cancer. (2019)
  • Author(s): Nakanishi Y, Masuda T, Yamaguchi K, Sakamoto S, Horimasu Y, Nakashima T, Miyamoto S, Tsutani Y, Iwamoto H, Fujitaka K, Miyata Y, Hamada H, Okada M, Hattori N.
  • Journal Title: Respir Investig. Volume: 57 Issue: 5 Pages: 451-459
  • DOI: 10.1016/j.resinv.2019.05.002
  • Peer Reviewed
• [Journal Article] C-C Motif Chemokine Ligand 15 May Be a Useful Biomarker for Predicting the Prognosis of Patients with Chronic Hypersensitivity Pneumonitis. (2019)
  • Author(s): Watanabe M, Horimasu Y, Iwamoto H, Yamaguchi K, Sakamoto S, Masuda T, Nakashima T, Miyamoto S, Ohshimo S, Fujitaka K, Hamada H, Kohno N, Hattori N.
  • Journal Title: Respiration. Volume: 98 Issue: 3 Pages: 212-220
  • DOI: 10.1159/000500576
  • Peer Reviewed
• [Journal Article] Chemotherapy-associated Acute Exacerbation of Interstitial Lung Disease Shortens Survival Especially in Small Cell Lung Cancer. (2019)
  • Author(s): Nakao S, Yamaguchi K, Sakamoto S, Horimasu Y, Masuda T, Miyamoto S, Nakashima T, Iwamoto H, Fujitaka K, Hamada H, Hattori N.
  • Journal Title: Anticancer Res. Volume: 39 Issue: 10 Pages: 5725-5731
  • DOI: 10.21873/anticanres.13773
  • Peer Reviewed
• [Journal Article] Anti-KL-6/MUC1 monoclonal antibody reverses resistance to trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity by capping MUC1. (2019)
  • Author(s): Namba M, Hattori N, Hamada H, Yamaguchi K, Okamoto Y, Nakashima T, Masuda T, Sakamoto S, Horimasu Y, Miyamoto S, Iwamoto H, Fujitaka K, Kohno N.
  • Journal Title: Cancer Letter Volume: 442 Pages: 31-39
  • Peer Reviewed
• [Journal Article] High preoperative C-reactive protein level is a risk factor for acute exacerbation of interstitial lung disease after non-pulmonary surgery (2019)
  • Author(s): Takao Shun、Masuda Takeshi、Yamaguchi Kakuhiro、Sakamoto Shinjiro、Horimasu Yasushi、Nakashima Taku、Miyamoto Shintaro、Iwamoto Hiroshi、Fujitaka Kazunori、Hamada Hironobu、Hattori Noboru
  • Journal Title: Medicine Volume: 98 Issue: 5 Pages: e14296-e14296
  • DOI: 10.1097/md.0000000000014296
  • Peer Reviewed / Open Access
• [Journal Article] Aminopeptidase N/CD13 as a Potential Therapeutic Target in Malignant Pleural Mesothelioma (2018)
  • Author(s): Otsuki Takahiko、Nakashima Taku、Hamada Hironobu、Takayama Yusuke、Akita Shin、Masuda Takeshi、Horimasu Yasushi、Miyamoto Shintaro、Iwamoto Hiroshi、Fujitaka Kazunori、Miyata Yoshihiro、Miyake Masayuki、Kohno Nobuoki、Okada Morihito、Hattori Noboru
  • Journal Title: European Respiratory Journal Volume: 51 Issue: 5 Pages: 1701610-1701610
  • DOI: 10.1183/13993003.01610-2017
  • Peer Reviewed
• [Journal Article] Nivolumab-induced severe pancytopenia in a patient with lung adenocarcinoma (2018)
  • Author(s): Tokumo Kentaro、Masuda Takeshi、Miyama Takahiko、Miura Shinichiro、Yamaguchi Kakuhiro、Sakamoto Shinjiro、Horimasu Yasushi、Nakashima Taku、Miyamoto Shintaro、Yoshida Takashi、Iwamoto Hiroshi、Fujitaka Kazunori、Hamada Hironobu、Hattori Noboru
  • Journal Title: Lung Cancer Volume: 119 Pages: 21-24
  • DOI: 10.1016/j.lungcan.2018.02.018
  • Peer Reviewed
• [Journal Article] Intratracheal Administration of siRNA Dry Powder Targeting Vascular Endothelial Growth Factor Inhibits Lung Tumor Growth in Mice (2018)
  • Author(s): Miwata Kei、Okamoto Hirokazu、Nakashima Taku、Ihara Daisuke、Horimasu Yasushi、Masuda Takeshi、Miyamoto Shintaro、Iwamoto Hiroshi、Fujitaka Kazunori、Hamada Hironobu、Shibata Ayumi、Ito Takaaki、Okuda Tomoyuki、Hattori Noboru
  • Journal Title: Molecular Therapy - Nucleic Acids Volume: 12 Pages: 698-706
  • DOI: 10.1016/j.omtn.2018.07.009
  • Peer Reviewed / Open Access
• [Journal Article] Bevacizumab with Single-agent Chemotherapy in Previously Treated Non-squamous Non-small-cell Lung Cancer: Phase II Study (2018)
  • Author(s): YAMAGUCHI KAKUHIRO、MASUDA TAKESHI、FUJITAKA KAZUNORI、MIWATA KEI、SAKAMOTO SHINJIRO、HORIMASU YASUSHI、HAMAI KOSUKE、MIYAMOTO SHINTARO、NAKASHIMA TAKU、OKAMOTO YOHEI、IWAMOTO HIROSHI、ISHIKAWA NOBUHISA、MIYATA YOSHIHIRO、OKADA MORIHITO、HAMADA HIRONOBU、HATTORI NOBORU
  • Journal Title: In Vivo Volume: 32 Issue: 5 Pages: 1155-1160
  • DOI: 10.21873/invivo.11358
  • Peer Reviewed
• [Journal Article] Plasminogen activator inhibitor-1 serves an important role in radiation-induced pulmonary fibrosis (2018)
  • Author(s): Shioya Sachiko、Masuda Takeshi、Senoo Tadashi、Horimasu Yasushi、Miyamoto Shintaro、Nakashima Taku、Iwamoto Hiroshi、Fujitaka Kazunori、Hamada Hironobu、Hattori Noboru
  • Journal Title: Experimental and Therapeutic Medicine Volume: 16 Pages: 3070-3076
  • DOI: 10.3892/etm.2018.6550
  • Peer Reviewed
• [Journal Article] Alternate-day administration of S-1 for elderly patients with advanced non-small-cell lung carcinoma: A prospective feasibility study (2018)
  • Author(s): Masuda Takeshi、Watanabe Masako、Fujitaka Kazunori、Hamai Kosuke、Ishikawa Nobuhisa、Doi Mihoko、Kitaguchi Soichi、Yamaguchi Kakuhiro、Sakamoto Shinjiro、Horimasu Yasushi、Miyamoto Shintaro、Nakashima Taku、Senoo Tadashi、Iwamoto Hiroshi、Hamada Hironobu、Hattori Noboru
  • Journal Title: Molecular and Clinical Oncology Volume: 9 Pages: 539-544
  • DOI: 10.3892/mco.2018.1705
  • Peer Reviewed
• [Journal Article] Serial measurements of KL-6 for monitoring activity and recurrence of interstitial pneumonia with anti-aminoacyl-tRNA synthetase antibody (2018)
  • Author(s): Yamaguchi Kakuhiro、Iwamoto Hiroshi、Sakamoto Shinjiro、Horimasu Yasushi、Masuda Takeshi、Miyamoto Shintaro、Nakashima Taku、Ohshimo Shinichiro、Fujitaka Kazunori、Hamada Hironobu、Kohno Nobuoki、Hattori Noboru
  • Journal Title: Medicine Volume: 97 Issue: 49 Pages: e13542-e13542
  • DOI: 10.1097/md.0000000000013542
  • Peer Reviewed / Open Access
• [Journal Article] Clinically remitted childhood asthma is associated with airflow obstruction in middle-aged adults. (2017)
  • Author(s): Omori K, Iwamoto H, Yamane T, Nakashima T, Haruta Y, Hattori N, Yokoyama A, Kohno N
  • Journal Title: Respirology Volume: 22 Issue: 1 Pages: 86-92
  • DOI: 10.1111/resp.12860
  • Peer Reviewed
• [Journal Article] Suplatast tosilate protects the lung against hyperoxic lung injury by scavenging hydroxyl radicals. (2017)
  • Author(s): Fukuhara K, Nakashima T, Abe M, Masuda T, Hamada H, Iwamoto H, Fujitaka K, Kohno N, Hattori N.
  • Journal Title: Free Radic Biol Med Volume: 106 Pages: 1-9
  • DOI: 10.1016/j.freeradbiomed.2017.02.014
  • Peer Reviewed
• [Journal Article] [A Case of Central Diabetes Insipidus That Was Caused by Pituitary Metastasis of Lung Adenocarcinoma and Was Controlled by Radiation Therapy]. (2017)
  • Author(s): Izumi Y, Masuda T, Nabeshima S, Horimasu Y, Nakashima T, Miyamoto S, Iwamoto H, Fujitaka K, Murakami Y, Hamada H, Nagata Y, Hattori N.
  • Journal Title: Gan To Kagaku Ryoho Volume: 44 Pages: 513-516
  • Peer Reviewed
• [Journal Article] Chronic Intestinal Pseudo-obstruction and Orthostatic Hypotension Associated with Small Cell Lung Cancer that Improved with Tumor Reduction after Chemoradiotherapy (2017)
  • Author(s): Izumi Y, Masuda T, Horimasu Y, Nakashima T, Miyamoto S, Iwamoto H, Fujitaka K, Hamada H, Hattori N.
  • Journal Title: Internal Medicine Volume: 56 Issue: 19 Pages: 2627-2631
  • DOI: 10.2169/internalmedicine.8574-16
  • NAID: 130006110679
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access
• [Journal Article] Additional Octreotide Therapy to Sirolimus Achieved a Decrease in Sirolimus-refractory Chylous Effusion Complicated with Lymphangioleiomyomatosis (2017)
  • Author(s): Namba M, Masuda T, Nakamura T, Horimasu Y, Miyamoto S, Nakashima T, Iwamoto H, Fujitaka K, Hamada H, Hattori N.
  • Journal Title: Internal Medicine Volume: 56 Issue: 24 Pages: 3327-3331
  • DOI: 10.2169/internalmedicine.8645-16
  • NAID: 130006250509
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access
• [Journal Article] The extent of ground-glass attenuation is a risk factor of chemotherapy-related exacerbation of interstitial lung disease in patients with non-small cell lung cancer (2017)
  • Author(s): Masuda Takeshi, Hirano Chihiro, Horimasu Yasushi, Nakashima Taku, Miyamoto Shintarou, Iwamoto Hiroshi, Ohshimo Shinichiro, Fujitaka Kazunori, Hamada Hironobu, Hattori Noboru
  • Journal Title: Cancer Chemotherapy and Pharmacology Volume: 81 Issue: 1 Pages: 131-139
  • DOI: 10.1007/s00280-017-3476-5
  • Peer Reviewed
• [Journal Article] AGER rs2070600 polymorphism elevates neutrophil-lymphocyte ratio and mortality in metastatic lung adenocarcinoma (2017)
  • Author(s): Yamaguchi K, Iwamoto H, Ohshimo S, et al.
  • Journal Title: Oncotarget Volume: 8 Issue: 55 Pages: 94382-94392
  • DOI: 10.18632/oncotarget.21764
  • Peer Reviewed / Open Access
• [Presentation] IPF患者におけるBALF中endogenous secretary RAGEの検討 (2019)
  • Author(s): 三浦 慎一朗、山口 覚博、坂本 信二郎、堀益 靖、益田 武、宮本 真太郎、中島 拓、岩本 博志、藤高 一慶、濱田 泰伸、服部 登
  • Organizer: 第59回日本呼吸器学会学術講演会
• [Presentation] 間質性肺炎合併肺癌における全身化学療法による間質性肺炎急性増悪が予後に与える影響についての検討 (2019)
  • Author(s): 中尾 聡志、山口 覚博、坂本 信二郎、堀益 靖、益田 武、宮本 真太郎、中島 拓、岩本 博志、藤高 一慶、濱田 泰伸、服部 登
  • Organizer: 第59回日本呼吸器学会学術講演会
• [Presentation] 呼吸音の可視化・解析システムの臨床応用へ向けた検討―間質性肺炎の診断における有用性― (2019)
  • Author(s): 堀益 靖、大下 慎一郎、岩本 博志、山口 覚博、坂本 信二郎、益田 武、中島 拓、宮本 真太郎、藤高 一慶、貞森 拓磨、志馬 伸朗、濱田 泰伸、服部 登
  • Organizer: 第59回日本呼吸器学会学術講演会
• [Presentation] IPF患者における血中High mobility group box 1の検討 (2019)
  • Author(s): 山口 覚博、岩本 博志、坂本 信二郎、堀益 靖、益田 武、中島 拓、宮本 真太郎、藤高 一慶、濱田 泰伸、服部 登
  • Organizer: 第59回日本呼吸器学会学術講演会
• [Presentation] スプラタストトシル酸塩による放射線肺障害の抑制効果 (2019)
  • Author(s): 泉 祐介、中島 拓、益田 武、塩谷 咲千子、福原 和秀、山口 覚博、坂本 信二郎、堀益 靖、宮本 真太郎、岩本 博志、藤高 一慶、濱田 泰伸、服部 登
  • Organizer: 第59回日本呼吸器学会学術講演会
• [Presentation] PAI-1 Influences the Effectiveness of Chemotherapy Through Its Association with Apoptosis in Cancer-Associated Myofibroblasts (2018)
  • Author(s): T. Masuda, T. Nakashima, M. Namba, K. Yamaguchi, S. Sakamoto, Y. Horimasu, S. Miyamoto, H. Iwamoto, K. Fujitaka, H. Hamada, N. Hatttori
  • Organizer: American Thoracic Society 2018
  • Int'l Joint Research
• [Presentation] Vascular Endothelial Growth Factor Knockdown by Intratracheal Administration of Small-Interfering RNA Dry Powder Inhibits Tumor Growth in a Mouse Lung Metastasis Model (2018)
  • Author(s): K. Miwata, Y. Horimasu, T. Masuda, S. Miyamoto, T. Nakashima, H. Iwamoto, K. Fujitaka, H. Hamada, N. Hattori
  • Organizer: American Thoracic Society 2018
  • Int'l Joint Research
• [Presentation] Extent of the Honeycombing Area and the Presence of Traction Bronchiectasis Are Risk Factors for Poorer Prognosis in Patients with Pleuroparenchymal Fibroelastosis (2018)
  • Author(s): M. Namba, T. Masuda, K. Yamaguchi, S. Sakamoto, Y. Horimasu, S. Miyamoto, T. Nakashima, H. Iwamoto, S. Ohshimo, K. Fujitaka, H. Hamada, N. Hattori
  • Organizer: American Thoracic Society 2018
  • Int'l Joint Research
• [Presentation] IPFの遺伝子素因―MUC5B遺伝子多型を中心に (2018)
  • Author(s): 堀益 靖、山口 覚博、坂本 信二郎、益田 武、中島 拓、岩本 博志、藤高 一慶、服部 登
  • Organizer: 第58回日本呼吸器学会学術講演会
  • Invited
• [Presentation] 癌関連線維芽細胞の筋線維芽細胞への分化による腫瘍進展促進：PAI-1の関与の検討 (2018)
  • Author(s): 益田 武、難波 将史、中島 拓、堀益 靖、宮本 真太郎、岩本 博志、藤高 一慶、濱田 泰伸、服部 登
  • Organizer: 第58回日本呼吸器学会学術講演会
• [Presentation] 特発性とARS抗体陽性の非特異性間質性肺炎における臨床的特徴の検討 (2018)
  • Author(s): 塩谷 咲千子、益田 武、山口 覚博、坂本 信二郎、堀益 靖、宮本 真太郎、中島 拓、岩本 博志、藤高 一慶、濱田 泰伸、服部 登
  • Organizer: 第58回日本呼吸器学会学術講演会
• [Presentation] 肺外臓器手術後の間質性肺炎急性増悪発症に対するリスク因子の検討 (2018)
  • Author(s): 高尾 俊、益田 武、山口 覚博、坂本 信二郎、堀益 靖、宮本 真太郎、中島 拓、岩本 博志、藤高 一慶、濱田 泰伸、服部 登
  • Organizer: 第58回日本呼吸器学会学術講演会
• [Presentation] CHP患者におけるBALFおよび血中のCCL15の検討 (2018)
  • Author(s): 渡部 雅子、堀益 靖、岩本 博志、山口 覚博、坂本 信二郎、益田 武、宮本 真太郎、中島 拓、大下 慎一郎、藤高 一慶、濱田 泰伸、服部 登
  • Organizer: 第58回日本呼吸器学会学術講演会
• [Presentation] IPF患者における血中endogenous secretary RAGEの検討 (2018)
  • Author(s): 山口 覚博、岩本 博志、坂本 信二郎、堀益 靖、益田 武、中島 拓、宮本 真太郎、大下 慎一郎、藤高 一慶、濱田 泰伸、服部 登
  • Organizer: 第58回日本呼吸器学会学術講演会
• [Presentation] 抗PD-1抗体による薬剤性間質性肺疾患の発症に対するリスク因子の検討 (2018)
  • Author(s): 中西 雄、益田 武、堀益 靖、宮本 真太郎、中島 拓、岩本 博志、藤高 一慶、濱田 泰伸、服部 登
  • Organizer: 第58回日本呼吸器学会学術講演会
• [Presentation] 留学のすすめ/留学を考えているヒトへの処方箋 (2017)
  • Author(s): 中島拓
  • Organizer: 第58回日本呼吸器学会中国・四国地方会
  • Invited
• [Book] 呼吸器内科．「ARDSのすべて」: ARDSの血清マーカー (2018)
  • Author(s): 中島 拓，服部 登
  • Total Pages: 6
  • Publisher: 科学評論社
• [Book] 呼吸器内科．「間質性肺炎・肺線維症のトピックス」: 注目される新規バイオマーカー (2018)
  • Author(s): 中島 拓，服部 登
  • Total Pages: 7
  • Publisher: 科学評論社
• [Book] 間質性肺炎・肺線維症と類縁疾患．治療の目標と管理 (2018)
  • Author(s): 中島 拓，服部 登
  • Total Pages: 6
  • Publisher: 中山書店
• [Book] 今日の診断指針 第8版． 「疾患編」: 慢性好酸球性肺炎 (Chronic Eosinophilic Pneumonia) (2018)
  • Author(s): 中島 拓
  • Total Pages: 2
  • Publisher: 医学書院