Investigating the drugs to repair injured alveolar epithelial cells using type 2 alveolar epithelial progenitor cells with ABCA3 mutations

• Project/Area Number: 16K10056
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Tohoku University
• Principal Investigator: Ota Chiharu 東北大学, 大学病院, 助教 (00733106)
• Co-Investigator(Kenkyū-buntansha): 菊池 敦生 東北大学, 大学病院, 助教 (30447156) ; 丹藤 由希子 東北大学, 加齢医学研究所, JSPS特別研究員(RPD) (70596212) ; 木村 正人 東北大学, 大学病院, 助教 (80646894)
• Project Period (FY): 2016-04-01 – 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 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 肺胞上皮細胞 / 遺伝性間質性肺炎 / ABCA3 / 肺胞上皮前駆細胞 / 肺胞傷害 / 肺胞修復 / 肺線維化 / 分化誘導法 / サーファクタント / 小児 / 肺胞上皮幹細胞 / 薬物スクリーニング / 薬剤スクリーニング / FACS / サーファクタント蛋白 / 2型肺胞上皮細胞 / 小児間質性肺炎

Outline of Final Research Achievements

Patients with homozygous or compound heterozygous mutations in ABCA3 gene cause severe lung diseases in infants and children. We isolated an alveolar epithelial progenitor cells (AEPCs) from human lungs. In the present study, we isolated AEPCs from 2 patients without ABCA3 mutations and from 2 patients with different ABCA3 mutations and analyzed the differentially expressed genes of the two groups.
We evaluated the differentially expressed genes of AT2 derived from ABCA3-wt- and ABCA3-mt-AEPCs. Changes of cell polarity and epithelial barrier function, development associated genes in AT2 with ABCA3 mutation might be involved in the disease development.

Academic Significance and Societal Importance of the Research Achievements

本研究の成果は，ABCA3変異によって起こっていると考えられる肺胞上皮細胞(AT2) 機能障害を，AT2 の前駆細胞AEPCsを用いて再現したところである．本研究の成果を用い，ABCA3変異によって生じるAT2機能障害をターゲットとして，AT2 の機能を改善するという新規視点による治療薬開発を目指すことができる．また，ABCA3 は肺ではAT2 に特異的な遺伝子であるため，ABCA3変異の解析はAT2傷害による難治性肺疾患のメカニズム解明につながる可能性がある．

Research Products

• [Int'l Joint Research] Dr. von Hauner Children’s Hospital(ドイツ)
• [Journal Article] Improving the viability of tissue‐resident stem cells using an organ‐preservation solution (2019)
  • Author(s): Suzuki Takaya、Ota Chiharu、Fujino Naoya、Tando Yukiko、Suzuki Satoshi、Yamada Mitsuhiro、Kondo Takashi、Okada Yoshinori、Kubo Hiroshi
  • Journal Title: FEBS Open Bio Volume: 9 Issue: 12 Pages: 2093-2104
  • DOI: 10.1002/2211-5463.12748
  • Peer Reviewed / Open Access
• [Journal Article] Preoperative administration of propranolol reduced the surgical risks of PHACES syndrome in a 14-month-old girl (2019)
  • Author(s): Rokugo Yuka、Ota Chiharu、Kimura Masato、Sasahara Yoji
  • Journal Title: BMJ Case Reports Volume: 12 Issue: 4 Pages: e228117-e228117
  • DOI: 10.1136/bcr-2018-228117
• [Journal Article] Dynamic expression of HOPX in alveolar epithelial cells reflects injury and repair during the progression of pulmonary fibrosis (2018)
  • Author(s): Ota Chiharu、Ng-Blichfeldt John-Poul、Korfei Martina、Alsafadi Hani N.、Lehmann Mareike、Skronska-Wasek Wioletta、M. De Santis Martina、Guenther Andreas、Wagner Darcy E.、K?nigshoff Melanie
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 1-10
  • DOI: 10.1038/s41598-018-31214-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Differential effects of Nintedanib and Pirfenidone on lung alveolar epithelial cell function in ex vivo murine and human lung tissue cultures of pulmonary fibrosis (2018)
  • Author(s): Lehmann Mareike、Buhl Lara、Alsafadi Hani N.、Klee Stephan、Hermann Sarah、Mutze Kathrin、Ota Chiharu、Lindner Michael、Behr J?rgen、Hilgendorff Anne、Wagner Darcy E.、K?nigshoff Melanie
  • Journal Title: Respiratory Research Volume: 19 Issue: 1 Pages: 1-12
  • DOI: 10.1186/s12931-018-0876-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Asymptomatic left atrial appendage aneurysm (LAAA) with pericardial defect in a 1-year-old girl (2018)
  • Author(s): Ota Chiharu、Kimura Masato、Kitami Masahiro、Kure Shigeo
  • Journal Title: BMJ Case Reports Volume: bcr～2018-224573 Pages: 1-2
  • DOI: 10.1136/bcr-2018-224573
• [Journal Article] Expression of cytochrome P450 mRNAs in Type II alveolar cells from subjects with chronic obstructive pulmonary disease. (2018)
  • Author(s): Kamata S, Fujino N, Yamada M, Grime K, Suzuki S, Ota C, Tando Y, Okada Y, Sakurada A, Noda M, Matsuda Y, Sugiura H, Ichinose M.
  • Journal Title: Pharmacol Res Perspect. Volume: 6 Pages: 1-7
• [Journal Article] Senolytic drugs target alveolar epithelial cell function and attenuate experimental lung fibrosis ex vivo (2017)
  • Author(s): Lehmann M, Korfei M, Mutze K, Klee S, Skronska-Wasek W, Alsafadi HN, Ota C, Costa R, Schiller HB, Lindner M, Wagner DE, Guenther A, Koenigshoff M
  • Journal Title: European Respiratory Journal Volume: 50 Issue: 2 Pages: 1-7
  • DOI: 10.1183/13993003.02367-2016
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 間質性肺炎に対し，脳死肺移植を施行した1歳女児例 (2019)
  • Author(s): 大田千晴
  • Organizer: 第19回東北びまん性肺疾患研究会
  • Invited
• [Presentation] ABCA3変異に伴う遺伝性間質性肺炎に対し 脳死肺移植を行った女児例 (2019)
  • Author(s): 大田千晴，木村正人，岩澤伸哉，松田安史，岡田克典，齊藤涼子，呉 繁夫
  • Organizer: 第52回日本小児呼吸器学会
• [Presentation] 慢性肺疾患に合併した肺高血圧に対し 肺血管拡張薬投与が有効であった2例 (2018)
  • Author(s): 大田千晴，木村正人，荒川貴弘 呉 繁夫
  • Organizer: 日本小児呼吸器学会
• [Presentation] HOPX-WNT pathway regulates alveolar homeostasis (2017)
  • Author(s): Chiharu Ota, John-Poul Ng-Blichfeldt, Kathrin Mutze, Wioletta Skronska, Hoeke Baasma, Darcy Wagner, Melanie Koenigshoff
  • Organizer: American Thoracic Society
  • Int'l Joint Research
• [Presentation] Wnt activity marks lung progenitors capable of forming spheres in vitro (2017)
  • Author(s): John-Poul Ng-Blichfeldt, Chiharu Ota, Jan Stolk, Pieter Hiemstra, Reinoud Gosens, Melanie Koenigshoff
  • Organizer: American Thoracic Society
  • Int'l Joint Research