Development of novel cell therapy for severe pneumonia using induced-pulmonary epithelial-like cells via direct reprogramming technique

• Project/Area Number: 18K19566
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 54:Internal medicine of the bio-information integration and related fields
• 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): 2018-06-29 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2019: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2018: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: 直接リプログラミング / 肺上皮細胞 / 再生 / 細胞治療 / インフルエンザ / 肺炎球菌

Outline of Final Research Achievements

Regenerative medicine approaches for repairing or replacing damaged lung tissue induced by inflammatory lung disease such as severe pneumonia have been needed. Direct reprogramming from terminally differentiated cells to pulmonary epithelial cells is an emerging technique; however, there has been no report which demonstrate success of induction of pulmonary epithelial cells. Here, we have succeeded direct conversion to surfactant protein C (SP-C)-positive pulmonary epithelial-like cells from mouse fibroblast by defined four factors. Intratracheal injection of the induced pulmonary epithelial cells resulted in protection against influenza virus infection and decreased viral load in mice. In addition, some of the injected cells attached on bronchial surface, indicating that some injected cells contribute to regeneration of injured tissue.

Academic Significance and Societal Importance of the Research Achievements

本研究は、直接リプログラミングによる肺上皮様細胞の誘導に初めて成功し、マウスモデルで再生の可能性を示した。従来の再生医療はiPS細胞などの幹細胞を用いたアプローチであるが、直接リプログラミングによる肺上皮細胞誘導の成功により、これまでiPS細胞が担ってきた、再生工学、薬剤スクリーニング、そして患者から直接リプログラミングにより誘導した疾患特異的肺上皮細胞を用いた病態研究にも応用が可能である。さらに、生体内にリプログラミング因子を導入することで生体内直接リプログラミングによる肺線維症に対する新規治療の可能性も広がる。ヒトでの直接リプログラミングも検討中であり実臨床応用に向けて重要な知見である。

Research Products

• [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
• [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] Obesity worsens the outcome of influenza virus infection associated with impaired type I interferon induction in mice (2019)
  • Author(s): Namkoong Ho、Ishii Makoto、Fujii Hideki、Asami Takahiro、Yagi Kazuma、Suzuki Shoji、Azekawa Shuhei、Tasaka Sadatomo、Hasegawa Naoki、Betsuyaku Tomoko
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 513 Issue: 2 Pages: 405-411
  • DOI: 10.1016/j.bbrc.2019.03.211
• [Presentation] Direct reprogramming of mouse fibroblasts into pulmonary epithelial-like cells. (2019)
  • Author(s): 7.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