Development of a direct induction method for human lung epithelial cells by reprogramming and elucidation of its molecular basis

• Project/Area Number: 18H02821
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Keio University
• Principal Investigator: ISHII Makoto 慶應義塾大学, 医学部(信濃町), 准教授 (30317333)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000); Fiscal Year 2020: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2019: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2018: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
• Keywords: 直接リプログラミング / 肺上皮細胞 / 再生

Outline of Final Research Achievements

Our group was the first to successfully induce type 2 alveolar epithelial cells in mice by direct reprogramming using specific four factors. In the present study, we attempted to directly induce human type 2 alveolar epithelial cells using human SFTPC reporter fibroblasts. From 16 candidate factors selected, 3 factors were finally selected as reprogramming factors by combination experiments of transcription factors. The detailed genetic profile of these induced SFTPC-positive cells will be investigated in the near future.

Academic Significance and Societal Importance of the Research Achievements

今後、今回誘導に成功した誘導細胞の遺伝子発現プロファイルを検討することで、2型肺胞上皮細胞により近似した細胞であるかを確認する。直接リプログラミングにより、ヒトで誘導2型肺胞上皮細胞誘導に成功したことが確認できれば、iPS細胞から誘導する方法に比べて、短期間かつ腫瘍形成性の可能性が低い新規の誘導方法として重要な意義がある。具体的には、難治性呼吸器疾患（慢性閉塞性肺疾患等）に対する誘導細胞による細胞治療、誘導細胞を用いた新規薬剤の毒性スクリーニング試験、疾患特異的な誘導細胞を用いた疾患病態機序の解明等のiPS細胞が現在担っている役割の少なくとも一部を担うことが可能となる。

Research Products

• [Journal Article] Genome-wide association study in patients with pulmonary Mycobacterium avium complex disease (2021)
  • Author(s): Ho Namkoong, Yosuke Omae, Takanori Asakura, Makoto Ishii, Shoji Suzuki, Kozo Morimoto, Yosuke Kawai, Katsura Emoto, Andrew J. Oler, Eva P. Szymanski, Mitsunori Yoshida, et al.
  • Journal Title: European Respiratory Journal Volume: 57 Issue: 2 Pages: 1902269-1902269
  • DOI: 10.1183/13993003.02269-2019
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Incomplete humoral response including neutralizing antibodies in asymptomatic to mild COVID-19 patients in Japan (2021)
  • Author(s): Takeshita Masaru、Nishina Naoshi、Moriyama Saya、Takahashi Yoshimasa、Uwamino Yoshifumi、Nagata Mika、Aoki Wataru、Masaki Katsunori、Ishii Makoto、Saya Hideyuki、Kondo Yasushi、Kaneko Yuko、Suzuki Katsuya、Fukunaga Koichi、Takeuchi Tsutomu
  • Journal Title: Virology Volume: 555 Pages: 35-43
  • DOI: 10.1016/j.virol.2020.12.020
  • Peer Reviewed
• [Journal Article] The real-time reverse transcription-polymerase chain reaction threshold cycle values for severe acute respiratory syndrome coronavirus 2 predict the prognosis of coronavirus disease 2019 pneumonia (2021)
  • Author(s): Fukushima Takahiro、Kabata Hiroki、Yamamoto Ryo、Suhara Tomohiro、Uwamino Yoshifumi、Kondo Yasushi、Masaki Katsunori、Kamata Hirofumi、Nagata Hiromasa、Homma Koichiro、Kaneko Yuko、Ishii Makoto、Sasaki Junichi、Morisaki Hiroshi、Hasegawa Naoki、Fukunaga Koichi
  • Journal Title: Respiratory Investigation Volume: ー Issue: 3 Pages: 360-363
  • DOI: 10.1016/j.resinv.2020.12.011
  • Peer Reviewed
• [Journal Article] Accuracy and stability of saliva as a sample for reverse transcription PCR detection of SARS-CoV-2. (2021)
  • Author(s): Uwamino Y, Nagata M, Aoki W, Fujimori Y, Nakagawa T, Yokota H, Sakai-Tagawa Y, Iwatsuki-Horimoto K, Shiraki T, Uchida S, Uno S, Kabata H, Ikemura S, Kamata H, Ishii M, Fukunaga K, Kawaoka Y, Hasegawa N, Murata M
  • Journal Title: J Clin Pathol Volume: 74(1) Issue: 1 Pages: 67-68
  • DOI: 10.1136/jclinpath-2020-206972
  • Peer Reviewed
• [Journal Article] Serum Krebs von den Lungen-6 level in the disease progression and treatment of Mycobacterium avium complex lung disease. (2021)
  • Author(s): Asakura T, Kimizuka Y, Nishimura T, Suzuki S, Namkoong H, Masugi Y, Sato Y, Ishii M, Hasegawa N.
  • Journal Title: Respirology. Volume: 26(1) Issue: 1 Pages: 112-119
  • DOI: 10.1111/resp.13886
  • Peer Reviewed
• [Journal Article] Left Ventricular Thrombus With COVID-19 Complication in a Patient With Dilated Cardiomyopathy (2021)
  • Author(s): Imaeda Shohei、Kabata Hiroki、Shiraishi Yasuyuki、Kamata Hirofumi、Tsuruta Hikaru、Yuasa Shinsuke、Ishii Makoto、Fukuda Keiichi、Fukunaga Koichi
  • Journal Title: CJC Open Volume: 3 Issue: 1 Pages: 124-126
  • DOI: 10.1016/j.cjco.2020.09.014
  • Peer Reviewed / Open Access
• [Journal Article] Clinical characteristics of 345 patients with coronavirus disease 2019 in Japan: A multicenter retrospective study (2020)
  • Author(s): Ishii Makoto、et al.
  • Journal Title: Journal of Infection Volume: 81 Issue: 5 Pages: e3-e5
  • DOI: 10.1016/j.jinf.2020.08.052
  • Peer Reviewed
• [Journal Article] Acute onset olfactory/taste disorders are associated with a high viral burden in mild or asymptomatic SARS-CoV-2 infections (2020)
  • Author(s): Nakagawara Kensuke、Masaki Katsunori、Uwamino Yoshifumi、Kabata Hiroki、Uchida Sho、Uno Shunsuke、Asakura Takanori、Funakoshi Takeru、Kanzaki Sho、Ishii Makoto、Hasegawa Naoki、Fukunaga Koichi
  • Journal Title: International Journal of Infectious Diseases Volume: 99 Pages: 19-22
  • DOI: 10.1016/j.ijid.2020.07.034
  • Peer Reviewed
• [Journal Article] Exposure to Cigarette Smoke Enhances the Stemness of Alveolar Type 2 Cells (2020)
  • Author(s): Tsutsumi Akihiro、Ozaki Mari、Chubachi Shotaro、Irie Hidehiro、Sato Minako、Kameyama Naofumi、Sasaki Mamoru、Ishii Makoto、Hegab Ahmed E.、Betsuyaku Tomoko、Fukunaga Koichi
  • Journal Title: American Journal of Respiratory Cell and Molecular Biology Volume: 63 Issue: 3 Pages: 293-305
  • DOI: 10.1165/rcmb.2019-0188oc
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] ADAM17 protects against elastase-induced emphysema by suppressing CD62L+ leukocyte infiltration in mice (2020)
  • Author(s): Suzuki Shoji、Ishii Makoto、Asakura Takanori、Namkoong Ho、Okamori Satoshi、Yagi Kazuma、Kamata Hirofumi、Kusumoto Tatsuya、Kagawa Shizuko、Hegab Ahmed E.、Yoda Masaki、Horiuchi Keisuke、Hasegawa Naoki、Betsuyaku Tomoko
  • Journal Title: American Journal of Physiology-Lung Cellular and Molecular Physiology Volume: 318 Issue: 6 Pages: L1172-L1182
  • DOI: 10.1152/ajplung.00214.2019
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Clinical significance of anti-glycopeptidolipid-core IgA antibodies in patients newly diagnosed with Mycobacterium avium complex lung disease (2020)
  • Author(s): Matsuda Shuichi、Asakura Takanori、Morimoto Kozo、Suzuki Shoji、Fujiwara Keiji、Furuuchi Koji、Osawa Takeshi、Namkoong Ho、Ishii Makoto、Kurashima Atsuyuki、Tatsumi Koichiro、Ohta Ken、Hasegawa Naoki、Sasaki Yuka
  • Journal Title: Respiratory Medicine Volume: 171 Pages: 106086-106086
  • DOI: 10.1016/j.rmed.2020.106086
  • Peer Reviewed
• [Journal Article] Optimizing the in vitro colony-forming assay for more efficient delineation of the interaction between lung epithelial stem cells and their niche (2020)
  • Author(s): Ozaki M、Kagawa S、Ishii M、Hegab AE.
  • Journal Title: Journal of Stem Cells and Regenerative Medicine Volume: 16 Issue: 2 Pages: 50-62
  • DOI: 10.46582/jsrm.1602009
  • Peer Reviewed
• [Journal Article] A case of non‐severe COVID ‐19 complicated by pulmonary embolism (2020)
  • Author(s): Akiyama Yuto、Horiuchi Kohei、Kondo Yasushi、Kabata Hiroki、Ishii Makoto、Fukunaga Koichi
  • Journal Title: Respirology Case Reports Volume: 8 Issue: 7
  • DOI: 10.1002/rcr2.622
  • Peer Reviewed
• [Journal Article] Exacerbation of immune thrombocytopaenia triggered by COVID-19 in patients with systemic lupus erythematosus (2020)
  • Author(s): Kondo Yasushi、Kaneko Yuko、Oshige Tatsuhiro、Fukui Hiroyuki、Saito Shuntaro、Okayama Mikio、Kamata Hirofumi、Ishii Makoto、Hasegawa Naoki、Fukunaga Koichi、Takeuchi Tsutomu
  • Journal Title: Annals of the Rheumatic Diseases Volume: ー Issue: 5 Pages: e77-e77
  • DOI: 10.1136/annrheumdis-2020-218157
  • Peer Reviewed
• [Journal Article] Coronavirus disease 2019-associated rapidly progressive organizing pneumonia with fibrotic feature (2020)
  • Author(s): Okamori Satoshi、Lee Ho、Kondo Yasushi、Akiyama Yuto、Kabata Hiroki、Kaneko Yuko、Ishii Makoto、Hasegawa Naoki、Fukunaga Koichi
  • Journal Title: Medicine Volume: 99 Issue: 35 Pages: e21804-e21804
  • DOI: 10.1097/md.0000000000021804
  • Peer Reviewed
• [Journal Article] Retrospective evaluation of natural course in mild cases of Mycobacterium avium complex pulmonary disease. (2019)
  • Author(s): Kimizuka Y, Hoshino Y, Nishimura T, Asami T, Sakakibara Y, Morimoto K, Maeda S, Nakata N, Abe T, Uno S, Namkoong H, Fujiwara H, Funatsu Y, Yagi K, Fujie T, Ishii M, Inase N, Iwata S, Kurashima A, Betsuyaku T, Hasegawa N; Non-Tuberculous Mycobacteriosis-Japan Research Consortium (NTM-JRC).
  • Journal Title: PLoS One. Volume: 14(4) Issue: 4 Pages: e0216034-e0216034
  • DOI: 10.1371/journal.pone.0216034
  • Peer Reviewed / Open Access
• [Journal Article] Low serum estradiol levels are related to Mycobacterium avium complex lung disease: a cross-sectional study. (2019)
  • Author(s): Uwamino Y, Nishimura T, Sato Y, Tamizu E, Asakura T, Uno S, Mori M, Fujiwara H, Ishii M, Kawabe H, Murata M, Hasegawa N.
  • Journal Title: BMC Infect Dis. Volume: 19(1) Issue: 1 Pages: 1055-1055
  • DOI: 10.1186/s12879-019-4668-x
  • Peer Reviewed / Open Access
• [Journal Article] Sitafloxacin-Containing Regimen for the Treatment of Refractory?Mycobacterium avium?Complex Lung Disease. (2019)
  • Author(s): Asakura T, Suzuki S,Fukano H, Okamori S, Kusumoto T, Uwamino Y, Ogawa T, So M, Uno S, Namkoong H, Yoshida M, Kamata H, Ishii M, Nishimura T, Hoshino Y, Hasegawa N.
  • Journal Title: Open forum infectious diseases Volume: 6 Issue: 4
  • DOI: 10.1093/ofid/ofz108
  • Peer Reviewed / Open Access
• [Presentation] 呼吸器感染症の病態解明に向けた基礎研究からのアプローチ．ハイインパクトリサーチシンポジウム (2020)
  • Author(s): 石井誠
  • Organizer: 日本感染症学会総会、シンポジウム
  • Invited
• [Presentation] インフルエンザの病態と重症化機序．インフルエンザ診療Up to date． (2020)
  • Author(s): 石井誠
  • Organizer: 日本呼吸器学会総会、シンポジウム.
  • Invited
• [Presentation] 日本における気管支拡張症の原因および健康関連QOLの実態調査 (2020)
  • Author(s): 石井誠
  • Organizer: 日本呼吸器学会総会
  • Invited
• [Presentation] COVID-19の重症化予測 (2020)
  • Author(s): 石井誠
  • Organizer: 第28回創薬薬理フォーラム、シンポジウム．
  • Invited
• [Presentation] 増加する肺非結核性抗酸菌症の臨床研究から得られた最近の知見 (2020)
  • Author(s): 石井誠
  • Organizer: 日本細菌学会総会、シンポジウム
  • Invited
• [Presentation] Direct reprogramming of mouse fibroblasts into pulmonary epithelial-like cells. (2019)
  • Author(s): Kusumoto T, Ishii M, Yotsukura M, Hegab AE, Saito F, Hamamoto J, Asakura T, Kamata H, Namkoong H, Suzuki S, Okamori S, Ogawa T, So M, Asamura H, Ieda M, Betsuyaku T.
  • Organizer: The 115th annual International Conference of American thoracic society.
  • Int'l Joint Research
• [Book] ダイレクトリプログラミング ～再生医療の新展開～ (2020)
  • Author(s): 石井誠、小川卓範 （分担執筆）（鈴木 淳史監修）
  • Total Pages: 316
  • Publisher: (株)エヌ・ティー・エス
  • ISBN: 9784860436711
• [Patent(Industrial Property Rights)] 体細胞から気道基底細胞への分化用試薬及びその使用 (2020)
  • Inventor(s): 石井誠、小川卓範
  • Industrial Property Rights Holder: 石井誠、小川卓範
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2021-030331
  • Filing Date: 2020