Identification of fibroblasts that differentiate into myofibroblasts and the control of organ fibrosis

• Project/Area Number: 16K08736
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: Iwashita Toshihide 浜松医科大学, 医学部, 教授 (00283432)
• Co-Investigator(Kenkyū-buntansha): 目黒 史織 浜松医科大学, 医学部, 助教 (40724290)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
• Keywords: Fibroblast / lung / fibrosis / pulmonary fibrosis / 線維芽細胞 / Sca1 / collagen / elastin / CD248 / integrin alpha 8 / 線維化 / 臓器線維症 / Thy1 / collagen 1a1 / 線維芽細胞のheterogeneity / 筋線維芽細胞 / 炎症

Outline of Final Research Achievements

To better understand the pathology and improve diagnosis and treatment of lung fibrosis, it is necessary to elucidate the nature of lung fibroblast heterogeneity and identify markers for the classification of human lung fibroblast subtypes. We characterized distinct mouse lung fibroblast subpopulations and performed microarray analysis to identify molecular markers. Based on the expression of these markers, in normal human lungs and idiopathic pulmonary fibrosis (IPF) lungs, two corresponding major fibroblast subtypes were identified: CD248-positive fibroblast and ITGA8-positive fibroblast, localized in the collagen fiber-rich connective tissue and in the elastic fiber-rich connective tissue, respectively. This human lung fibroblast classification may be helpful for further detailed investigations of the functions of lung fibroblast subtypes, which can provide new insights into lung development and the pathological processes underlying fibrotic lung diseases.

Academic Significance and Societal Importance of the Research Achievements

今回明らかにしたヒト肺線維芽細胞の分類システム（CD248陽性線維芽細胞およびITGA8陽性線維芽細胞）を使用して、異なる線維芽細胞の機能のさらなる詳細な調査を行うことができる。それは肺発生や特発性肺線維症だけではなく、非特異的間質性肺炎やおよびpleuroparenchymal fibroelastosisなどの他の線維性肺疾患の根底にある病理学的過程に関する新たな洞察を得るのに役立つと考えられる。

Research Products

• [Journal Article] Podoplanin-positive myofibroblasts: a pathological hallmark of pleuroparenchymal fibroelastosis. (2018)
  • Author(s): Enomoto Y, Matsushima S, Meguro S, Kawasaki H, Kosugi I, Fujisawa T, Enomoto N, Inui N, Nakamura Y, Suda T, Iwashita T.
  • Journal Title: Histopathology. Volume: 印刷中 Issue: 7 Pages: 1209-1215
  • DOI: 10.1111/his.13494
  • Peer Reviewed / Open Access
• [Journal Article] LTBP2 is secreted from lung myofibroblasts and is a potential biomarker for idiopathic pulmonary fibrosis (2018)
  • Author(s): Enomoto Yasunori、Matsushima Sayomi、Shibata Kiyoshi、Aoshima Yoichiro、Yagi Haruna、Meguro Shiori、Kawasaki Hideya、Kosugi Isao、Fujisawa Tomoyuki、Enomoto Noriyuki、Inui Naoki、Nakamura Yutaro、Suda Takafumi、Iwashita Toshihide
  • Journal Title: Clinical Science Volume: 132 Issue: 14 Pages: 1565-1580
  • DOI: 10.1042/cs20180435
  • Peer Reviewed / Open Access
• [Journal Article] MHC class I in dopaminergic neurons suppresses relapse to reward seeking (2018)
  • Author(s): Murakami G, Edamura M, Furukawa T, Kawasaki H, Kosugi I, Fukuda A, Iwashita T, Nakahara D
  • Journal Title: Science Advances Volume: 4 Issue: 3 Pages: 7388-7388
  • DOI: 10.1126/sciadv.aap7388
  • Peer Reviewed / Open Access
• [Journal Article] Immunohistochemical examination using the pericyte marker myosin 1B in a perivascular myoid tumor of soft tissue with definitive pericytic differentiation. (2018)
  • Author(s): Meguro S, Matsushima S, Enomoto Y, Kawasaki H, Kosugi I, Tsuchida T, Baba S, Fukamizu H, Yamato Y, Iwashita T.
  • Journal Title: Patholology International Volume: 69 Issue: 4 Pages: 246-248
  • DOI: 10.1111/pin.12777
  • Peer Reviewed / Open Access
• [Journal Article] Mesothelial/monocytic incidental cardiac excrescence with bone marrow. (2018)
  • Author(s): Yagi H, Takahashi S, Shinmura K, Iwashita T, Ogawa H.
  • Journal Title: Pathol Int. Volume: 印刷中 Issue: 7 Pages: 436-438
  • DOI: 10.1111/pin.12661
  • Peer Reviewed
• [Journal Article] Clinical diagnosis of idiopathic pleuroparenchymal fibroelastosis: A retrospective multicenter study. (2017)
  • Author(s): Enomoto Y, Nakamura Y, Satake Y, Sumikawa H, Johkoh T, Colby TV, Yasui H, Hozumi H, Karayama M, Suzuki Y, Furuhashi K, Fujisawa T, Enomoto N, Inui N, Iwashita T, Kuroishi S, Yokomura K, Koshimizu N, Toyoshima M, Imokawa S, Yamada T, Shirai T, Hayakawa H, Suda T.
  • Journal Title: Respir Med. Volume: 133 Pages: 1-5
  • DOI: 10.1016/j.rmed.2017.11.003
  • Peer Reviewed
• [Journal Article] A case of a primary hepatic so-called adenosarcoma with heterotopic ossification: possibly of biliary adenofibroma origin. (2017)
  • Author(s): Meguro S, Yamazaki S, Matsushima S, Kawata K, Kawasaki H, Tsuchida T, Kosugi I, Kobayashi Y, Baba S, Iwashita T.
  • Journal Title: Hum Pathol. Volume: 73 Pages: 108-113
  • DOI: 10.1016/j.humpath.2017.10.009
  • Peer Reviewed
• [Journal Article] Evaluation of epigenetic inactivation of vascular endothelial growth factor receptors in head and neck squamous cell carcinoma. (2017)
  • Author(s): Misawa Y, Misawa K, Kawasaki H, Imai A, Mochizuki D, Ishikawa R, Endo S, Mima M, Kanazawa T, Iwashita T, Mineta H.
  • Journal Title: Tumour Biol. Volume: 39 Issue: 7 Pages: 1-15
  • DOI: 10.1177/1010428317711657
  • Peer Reviewed / Open Access
• [Journal Article] Radiologic pleuroparenchymal fibroelastosis-like lesion in connective tissue disease-related interstitial lung disease. (2017)
  • Author(s): Enomoto Y, Nakamura Y, Colby TV, Johkoh T, Sumikawa H, Nishimoto K, Yoshimura K, Matsushima S, Oyama Y, Hozumi H, Kono M, Fujisawa T, Enomoto N, Inui N, Iwashita T, Suda T.
  • Journal Title: PLoS One Volume: 12 Issue: 6 Pages: e0180283-e0180283
  • DOI: 10.1371/journal.pone.0180283
  • Peer Reviewed / Open Access
• [Journal Article] Digoxin Attenuates Murine Experimental Colitis by Downregulating Th17-related Cytokines. (2017)
  • Author(s): Tani S, Takano R, Tamura S, Oishi S, Iwaizumi M, Hamaya Y, Takagaki K, Nagata T, Seto S, Horii T, Kosugi I, Iwashita T, Osawa S, Furuta T, Miyajima H, Sugimoto K.
  • Journal Title: Inflamm Bowel Dis. Volume: 23 Issue: 5 Pages: 728-738
  • DOI: 10.1097/mib.0000000000001096
  • Peer Reviewed
• [Journal Article] Phenotypic characterization of perivascular myoid cell neoplasms, using myosin 1B, a newly identified human pericyte marker (2017)
  • Author(s): Shiori Meguro, Taisuke Akamatsu, Sayomi Matsushima, Isao Kosugi, Hideya Kawasaki, Yoshifumi Arai, Satoshi Baba, Takashi Tsuchida, Yoji Shido, Takafumi Suda, Toshihide Iwashita
  • Journal Title: Human Pathology Volume: 62 Pages: 187-198
  • DOI: 10.1016/j.humpath.2016.12.024
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Clinical significance of soluble CD163 in polymyositis-related or dermatomyositis-related interstitial lung disease (2017)
  • Author(s): Enomoto Y, Suzuki Y, Hozumi H, Mori K, Kono M, Karayama M, Furuhashi K, Fujisawa T, Enomoto N, Nakamura Y, Inui N, Suzuki D, Ogawa N, Nakashima R, Mimori T, Iwashita T, Suda T
  • Journal Title: Arthritis Res Ther Volume: 19 Issue: 1 Pages: 9-9
  • DOI: 10.1186/s13075-016-1214-8
  • NAID: 120005973333
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Phenotypic characterization of perivascular myoid cell neoplasms, using myosin 1B, a newly identified human pericyte marker. (2017)
  • Author(s): Meguro S, Akamatsu T, Matsushima S, Kosugi I, Kawasaki H, Arai Y, Baba S, Tsuchida T, Shido Y, Suda T, Iwashita T.
  • Journal Title: Human Pathology Volume: 62 Pages: 187-198
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Pathogenesis of developmental anomalies of the central nervous system induced by congenital cytomegalovirus infection. (2017)
  • Author(s): Kawasaki H, Kosugi I, Meguro S, Iwashita T.
  • Journal Title: Pathol Int, Volume: 67 Pages: 72-82
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Pathogenesis of developmental anomalies of the central nervous system induced by congenital cytomegalovirus infection. (2016)
  • Author(s): Kawasaki H, Kosugi I, Meguro S, Iwashita T.
  • Journal Title: Pathol Int. Volume: 67(2) Issue: 2 Pages: 72-82
  • DOI: 10.1111/pin.12502
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Intracerebroventricular and Intravascular Injection of Viral Particles and Fluorescent Microbeads into the Neonatal Brain. (2016)
  • Author(s): Kawasaki H, Kosugi I, Sakao-Suzuki M, Meguro S, Tsutsui Y, Iwashita T.
  • Journal Title: J Vis Exp. Volume: 24;(113) Issue: 113 Pages: 113-113
  • DOI: 10.3791/54164
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] NanoSuit法を利用した高精度な迅速ウイルス粒子定量・同定法の開発、 (2017)
  • Author(s): 河崎秀陽、髙久康春、太田勲、小杉伊三夫、目黒史織、筒井祥博、針山孝彦、岩下寿秀、
  • Organizer: 第106回日本病理学会
• [Presentation] NanoSuit法を利用した高精度な迅速ウイルス定量・同定法の開発、 (2017)
  • Author(s): 河崎秀陽、髙久康春、太田勲、小杉伊三夫、目黒史織、岩下寿秀、針山孝彦、
  • Organizer: 第65回日本ウイルス学会学術集会
• [Presentation] マウス肺における異なった種類の線維芽細胞の同定 (2016)
  • Author(s): 松島 紗代実、目黒 史織、河崎 秀陽、小杉 伊三夫、岩下 寿秀
  • Organizer: 105回日本病理学会総会
  • Place of Presentation: 仙台
  • Year and Date: 2016-05-12