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] 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: - Issue: 6 Pages: L1172-L1182
  • DOI: 10.1152/ajplung.00214.2019
  • 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] 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