New Therapy for Intractable Pulmonary Fibrosis using Humoral Factors released from Mesenchymal Stem Cells

• Project/Area Number: 24591149
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Tohoku University
• Principal Investigator: OHKOUCHI Shinya 東北大学, 環境・安全推進センター, 講師 (40375035)
• Co-Investigator(Kenkyū-buntansha): EBINA Masahito 東北薬科大学, 病院, 教授 (10280885) ; 兼平 雅彦 東北大学, 大学病院, 助教 (90374941)
• Co-Investigator(Renkei-kenkyūsha): KANEHIRA Masahiko 東北大学, 大学院医学研究科, 助教 (90374941)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: 間葉系幹細胞 / 特発性肺線維症 / 間質性肺炎 / 小胞体ストレス / 過酸化ストレス / 骨髄間葉系幹細胞 / 液性因子 / 治療 / 成長因子 / TGF-BETA / STC1 / 国際情報交換 / ワルブルグ効果 / アメリカ合衆国

Outline of Final Research Achievements

Continuous ER-stress changes the secretary status of AECs and increase the synthesis, and secretion of pro-fibrotic humoral factors including TGF-beta 1 from AECs. TGF-beta 1 promotes the change from fibroblasts to myo-fibroblasts which is essential for the formation of fibrosis. Recent studies show that Mesenchymal stem cells (MSCs) ameliorate fibrosis in bleomycin inhalation mice (IPF model mice). MSCs can reduce ER-stress of cells in microenvironment under harmful conditions however that mechanism is still unknown. We has shown that protein hormone STC1 reduce endothelium reticulum stress (ER-stress) pulmonary fibrosis in Bleomycin-induced fibrosis mice. We published our work in Molecular Therapy, 2015, 23, 549.

Research Products

• [Journal Article] Mesenchymal Stem Cells Correct Inappropriate Epithelial-mesenchyme Relation in Pulmonary Fibrosis Using Stanniocalcin-1. (2015)
  • Author(s): Ono M, Ohkouchi S, Kanehira M, Tode N, Kobayashi M, Ebina M, Nukiwa T, Irokawa T, Ogawa H, Akaike T, Okada Y, Kurosawa H, Kikuchi T, Ichinose M.
  • Journal Title: Mol Ther Volume: 23 Issue: 3 Pages: 549-560
  • DOI: 10.1038/mt.2014.217
  • Peer Reviewed / Open Access
• [Journal Article] Human marrow stromal cells downsize the stem cell fraction of lung cancers by fibroblast growth factor 10. (2014)
  • Author(s): Kanehira M, Kikuchi T, Santoso A, Tode N, Hirano T, Ohkouchi S, Tamada T, Sugiura H, Harigae H, Ichinose M.
  • Journal Title: Mol Cell Biol Volume: 34 Issue: 15 Pages: 2848-56
  • DOI: 10.1128/mcb.00871-13
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis (2014)
  • Author(s): Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, Cottin V, Flaherty KR, Hansell DM, Inoue Y, Kim DS, Kolb M, Nicholson AG, Noble PW, Selman M, Taniguchi H, Brun M, Le Maulf F, Girard M, Stowasser S, Schlenker-Herceg R, Disse B, Collard HR
  • Journal Title: N Engl J Med Volume: 29 Issue: 22 Pages: 2071-82
  • DOI: 10.1056/nejmoa1402584
  • Peer Reviewed / Open Access
• [Journal Article] Duration of benefit in patients with autoimmune pulmonary alveolar proteinosis after inhaled granulocyte-macrophage colony-stimulating factor therapy. (2014)
  • Author(s): Tazawa R, Inoue Y, Arai T, Takada T, Kasahara Y, Hojo M, Ohkouchi S, Tsuchihashi Y, Yokoba M, Eda R, Nakayama H, Ishii H, Nei T, Morimoto K, Nasuhara Y, Ebina M, Akira M, Ichiwata T, Tatsumi K, Yamaguchi E, Nakata K.
  • Journal Title: Chest Volume: 145 Issue: 4 Pages: 729-737
  • DOI: 10.1378/chest.13-0603
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Development of pulmonary alveolar proteinosis following exposure to dust after the Great East Japan Earthquake. (2013)
  • Author(s): Hisata S, Moriyama H, Tazawa R, Ohkouchi S, Ichinose M, Ebina M.
  • Journal Title: Respir Investig Volume: 51 Issue: 4 Pages: 212-216
  • DOI: 10.1016/j.resinv.2013.04.005
  • Peer Reviewed
• [Journal Article] Deterioration in regional health status after the acute phase of a great disaster: respiratory physicians' experiences of the Great East Japan Earthquake. (2013)
  • Author(s): Ohkouchi S, Shibuya R, Yanai M, Kikuchi Y, Ichinose M, Nukiwa T.
  • Journal Title: Respir Investig. Volume: 51 Issue: 2 Pages: 50-55
  • DOI: 10.1016/j.resinv.2012.12.003
  • Peer Reviewed
• [Journal Article] Fatal acute interstitial pneumonia in a worker making chips from wooden debris generated by the Great East Japan earthquake and tsunami. (2012)
  • Author(s): Ohkouchi S, Ebina M, Kamei K, Moriyama H, Tamai T, Shibuya R, Ichinose M, Nukiwa T.
  • Journal Title: Respir Investig. Volume: 4 Issue: 4 Pages: 129-134
  • DOI: 10.1016/j.resinv.2012.09.001
  • Peer Reviewed
• [Presentation] The enhancement of Stanniocalcin-1 (STC1) secretion increases the ability of mesenchymal stem cells (MSCs) to reduce bleomycin-induced lung fibrosis in a mouse model through inhibition of endoplasmic reticulum stress (ER-stress)/TGFbeta1 pathway (2014)
  • Author(s): Shinya Ohkouchi, Manabu Ono and Masakazu Ichinose
  • Organizer: ERS international congress, 2014
  • Place of Presentation: Germany (Munich）
  • Year and Date: 2014-09-06 – 2014-09-10
• [Presentation] The Ability Of Mesenchymal Stem Cells (MSCs) Reducing Bleomycin-Induced Lung Fibrosis In Mice Model Through Inhibition Of ROS/Endoplasmic Reticulum Stress (ER-Stress)/TGFbeta1 Pathway (2014)
  • Author(s): Manabu O, Shinya O, Masahiko K, Naoki T, Toshiaki K, Masakazu I
  • Organizer: ATS international conference, 2014
  • Place of Presentation: USA （San Diego）
  • Year and Date: 2014-05-16 – 2014-05-21
• [Presentation] The Enhancement Of Stanniocalcin-1 (STC1) Secretion Increases The Ability Of Mesenchymal Stem Cells (MSCs) Reducing Bleomycin-Induced Lung Fibrosis In Mice Model Through Inhibition Of ROS/Endoplasmic Reticulum Stress (ER-Stress)/TGFβ1 Pathway (2014)
  • Author(s): M. Ono, graduate student, S. Ohkouchi, M.D. PhD., M. Kanehira, PhD, N. Tode, MD, T. Kikuchi, MD, PhD, M. Ichinose, Prof
  • Organizer: ATS 2014 San Diego
  • Place of Presentation: San Diego USA
• [Presentation] The enhancement of Stannniocalcin-1 (STC1) secretion of Multipotent-Stromal-Cells (MSCs) increases the ability to reduce bleomycin-induced lung injuries. (2013)
  • Author(s): Manabu Ono*, Shinya Ohkouchi, Masahiko Kanehira, Naoki Tode, Makoto Kobayashi, Tadahisa Numakura, Toshiaki Kikuchi and Masakazu Ichinose.
  • Organizer: APSR (Asian Pacific Society of Respirology) Annual Meeting 2013
  • Place of Presentation: yokohama
• [Presentation] Novel Functions Of Stanniocalcin-1(STC1) Through Uncoupling Protein 2 (UCP2) Up-Regulation; Promoting Survival Of Cancer Cells Under Oxidative Stress And Inducing The Uncoupling Respiration (Warburg Effect)
  • Author(s): Shinya Ohkouchi
  • Organizer: ATS 2012
  • Place of Presentation: San Francisco, USA
• [Presentation] The Enhancement Of Stannniocalcin-1 (STC1) Secretion Encourages The Abilities Of Mesenchymal Stem Cells (MSCs) Reducing Bleomycin Lung Injuries In Mice Model
  • Author(s): Ono M, Ohkouchi S
  • Organizer: ATS2013
  • Place of Presentation: Philadelphia, USA
• [Book] 治療薬Up-to-Date (2014)
  • Author(s): 共同執筆、監修・矢崎義雄、大河内眞也
  • Publisher: メディカルビュー
• [Book] イラスト呼吸器学 (2014)
  • Author(s): 共同執筆、編集・一ノ瀬正和、大河内眞也
  • Publisher: 文光堂
• [Patent(Industrial Property Rights)] PHARMACEUTICAL COMPOSITION FOR PREVENTION OR TREATING FIBROSIS (2014)
  • Inventor(s): Shinya Ohkouchi
  • Industrial Property Rights Holder: Shinya Ohkouchi
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-02-24
  • Overseas
• [Patent(Industrial Property Rights)] 線維症予防又は治療用医薬組成物 (2013)
  • Inventor(s): 大河内眞也
  • Industrial Property Rights Holder: 大河内眞也
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2011-152392
  • Filing Date: 2013-07-09
• [Patent(Industrial Property Rights)] PHARMACEUTICAL COMPOSITION FOR PREVENTION OR TREATING FIBROSIS (2013)
  • Inventor(s): Shinya Ohkouchi
  • Industrial Property Rights Holder: Shinya Ohkouchi
  • Industrial Property Rights Type: 特許
  • Filing Date: 2013-07-12
  • Overseas