Characterization of distal airway stem-like cells expressing N-terminally truncated p63 and thyroid transcription factor-1 in the human lung

• Project/Area Number: 17K16053
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Respiratory organ internal medicine
• Research Institution: Sapporo Medical University
• Principal Investigator: Tanaka Yusuke 札幌医科大学, 医学部, 研究員 (70792125)
• Research Collaborator: HIRAI sachie ; YAMAGUCHI miki ; SUMI toshiyuki ; TADA makoto ; SAITO atsushi ; CHIBA hirofumi ; KOJIMA takashi ; WATANABE atsushi ; TAKAHASHI hiroki ; SAKUMA yuji
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: Distal airway stem cell / 末梢肺上皮幹細胞 / TTF-1 / delta Np63 / 3次元培養 / ヒト末梢肺上皮幹細胞 / distal airway stem cell / 細胞・組織

Outline of Final Research Achievements

We found that human lung epithelial (HuL) cells, derived from normal, peripheral lung tissue, in monolayer, mostly express both the N-terminally truncated isoform of p63 (delta Np63), a marker for airway basal cells, and thyroid transcription factor-1 (TTF-1), a marker for alveolar epithelial cells, even though these two molecules are usually expressed in a mutually ex- clusive way. Three-dimensionally cultured HuL cells differentiated to form bronchiole-like and alveolus-like organoids. We also uncovered a few bronchiolar epithelial cells expressing both delta Np63 and TTF-1 in the human lung, suggesting that these cells are the cells of origin for HuL cells. Taken together, delta Np63+ TTF-1+ peripheral airway epithelial cells are possibly the human counterpart of mouse DASCs and may offer potential for future regenerative medicine.

Academic Significance and Societal Importance of the Research Achievements

呼吸器領域には，特発性肺線維症や慢性閉塞性肺疾患など根本的な治療法が存在しない慢性疾患が多く，iPS細胞で注目を集める“細胞治療”が将来的にこれら呼吸器領域の難病にも導入される可能性がある．肺は領域ごとにそれぞれ異なる上皮細胞が存在しているが，そのすべてに分化可能な上皮幹細胞の存在は明らかになっていなかった．本研究においてHuL細胞は末梢肺組織の複数部位の上皮細胞を再生しうる上皮幹細胞であることを明らかにすることができ，将来的に再生治療に使用しうる細胞と期待される．

Research Products

• [Journal Article] Characterization of distal airway stem-like cells expressing N-terminally truncated p63 and thyroid transcription factor-1 in the human lung. (2018)
  • Author(s): Tanaka Y, Yamaguchi M, Hirai S, Sumi T, Tada M, Saito A, Chiba H, Kojima T, Watanabe A, Takahashi H, Sakuma Y.
  • Journal Title: Exp Cell Res. Volume: 372(2) Issue: 2 Pages: 141-149
  • DOI: 10.1016/j.yexcr.2018.09.020
  • Peer Reviewed
• [Presentation] ヒト末梢気道幹細胞の研究 (2018)
  • Author(s): 田中悠祐、山口美樹、平井幸恵、角俊行、多田周、斎藤充史、千葉弘文、小島隆、渡辺敦、高橋弘毅、佐久間裕司
  • Organizer: 第58回日本呼吸器学会学術講演会
• [Presentation] Characterization of Distal Airway Stem Cells Expressing delta Np63 and TTF-1 in the Human Lung (2018)
  • Author(s): Yusuke Tanaka, Miki Yamaguchi, Sachie Hirai, Toshiyuki Sumi, Makoto Tada, Atsushi Saito, Hirofumi Chiba, Takashi Kojima, Atsushi Watanabe, Hiroki Takahashi, Yuji Sakuma
  • Organizer: International Rare Lung Diseases Conference
  • Int'l Joint Research
• [Presentation] ヒト末梢気道幹細胞の研究 (2018)
  • Author(s): 田中悠祐、山口美樹、平井幸恵、角俊行、多田周、斎藤充史、千葉弘文、小島隆、渡辺敦、高橋弘毅、佐久間裕司
  • Organizer: 第98回北海道医学大会病理分科会
• [Presentation] 末梢肺上皮幹細胞の基礎的研究 (2017)
  • Author(s): 田中悠祐，角俊行，山口美樹，平井幸恵，渡辺敦，高橋弘毅，佐久間裕司
  • Organizer: 第53回日本サーファクタント関連（界面）医学会