Analysis of fibroblast inprinting in lung injury

• Project/Area Number: 17K19546
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Pathology, Infection/Immunology, and related fields
• Research Institution: Tokyo University of Science (2018); The University of Tokyo (2017)
• Principal Investigator: Matsushima Kouji 東京理科大学, 研究推進機構生命医科学研究所, 教授 (50222427)
• Co-Investigator(Kenkyū-buntansha): 上羽 悟史 東京理科大学, 研究推進機構生命医科学研究所, 准教授 (00447385)
• Research Collaborator: Hashimoto Shinichi ; Shimaoka Takeshi ; Shichino Shigeyuki ; Nakajima Takuya ; Aoki Hiroyasu
• Project Period (FY): 2017-06-30 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2018: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2017: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
• Keywords: 病理学 / 免疫学 / 遺伝子 / 情報工学 / 線維芽細胞 / 養子移入 / トランスクリプトーム / プロテオグリカン

Outline of Final Research Achievements

Pulmonary fibrosis (PF) has a poor-prognosis, which characterized by the excess deposition of extracellular matrix produced mainly by activated lung fibroblasts. PF is often associated with chronic inflammation, which alters lung cell phenotype. However, how activated fibroblasts changes their phenotype through the course of lung injury is poorly known because limited options to assess fibroblast phenotype in vivo. By using intratracheal transfer method, we investigated the effect of origin of fibroblasts in their activation pattern and fibrosis pathology in bleomycin-induced lung injury. We found that the expression of Dcn was continuously downregulated after acute inflammation independently on fibroblast origin. In addition, adipose tissue-derived fibroblasts more strongly expressed Dcn, and both adipose tissue-derived and Dcn-overexpressed lung firboblast exert anti-inflammatory effect in bleomycin-induced lung injury.

Academic Significance and Societal Importance of the Research Achievements

本研究により、傷害された肺環境下に置かれた場合の線維芽細胞における遺伝子発現変動のなかで、組織の由来の違いによらず発現変動する遺伝子群、また由来組織の特徴が保持されている遺伝子群があることが明らかとなった。線維芽細胞の一種である間葉系幹細胞は様々な部位より採取されて、移植による疾患治療応用が試みられているが、本研究よりその部位の違いによりその効果が異なる可能性が想定されるので、間葉系幹細胞の社会応用のためにはその由来の考慮もまた必要な可能性がある。

Research Products

• [Journal Article] Transcriptome network analysis identifies protective role of the LXR/SREBP-1c axis in murine pulmonary fibrosis. (2019)
  • Author(s): Shichino S, Ueha S, Hashimoto S, Otsuji M, Abe J, Tsukui T, Deshimaru S, Nakajima T, Kosugi-Kanaya M, Shand FH, Inagaki Y, Shimano H, Matsushima K.
  • Journal Title: JCI Insight. Volume: 4(1) Issue: 1 Pages: 122163-122163
  • DOI: 10.1172/jci.insight.122163
  • Peer Reviewed / Open Access
• [Journal Article] Lung fibroblasts express a miR-19a-19b-20a sub-cluster to suppress TGF-β-associated fibroblast activation in murine pulmonary fibrosis (2018)
  • Author(s): Souma Kunihiko、Shichino Shigeyuki、Hashimoto Shinichi、Ueha Satoshi、Tsukui Tatsuya、Nakajima Takuya、Suzuki Hiroshi I.、Shand Francis H. W.、Inagaki Yutaka、Nagase Takahide、Matsushima Kouji
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 16642-16642
  • DOI: 10.1038/s41598-018-34839-0
  • Peer Reviewed / Open Access
• [Journal Article] Reduction of Proliferating Olfactory Cells and Low Expression of Extracellular Matrix Genes Are Hallmarks of the Aged Olfactory Mucosa. (2018)
  • Author(s): Ueha R, Shichino S, Ueha S, Kondo K, Kikuta S, Nishijima H, Matsushima K, Yamasoba T.
  • Journal Title: Front Aging Neurosci Volume: 10 Pages: 86-86
  • DOI: 10.3389/fnagi.2018.00086
  • Peer Reviewed / Open Access
• [Journal Article] Single blood transfusion induces the production of donor-specific alloantibodies and regulatory T cells mainly in the spleen. (2018)
  • Author(s): Ueta H, Kitazawa Y, Sawanobori Y, Ueno T, Ueha S, Matsushima K, Matsuno K.
  • Journal Title: Int Immunol Volume: 30 Issue: 2 Pages: 53-67
  • DOI: 10.1093/intimm/dxx078
  • Peer Reviewed / Open Access
• [Journal Article] Increased diversity with reduced "diversity evenness" of tumor infiltrating T-cells for the successful cancer immunotherapy. (2018)
  • Author(s): Hosoi A, Takeda K, Nagaoka K, Iino T, Matsushita H, Ueha S, Aoki S, Matsushima K, Kubo M, Morikawa T, Kitaura K, Suzuki R, Kakimi K.
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 1058-1058
  • DOI: 10.1038/s41598-018-19548-y
  • Peer Reviewed / Open Access
• [Journal Article] The HIV co-receptor CCR5 regulates osteoclast function. (2017)
  • Author(s): Lee JW, Hoshino A, Inoue K, Saitou T, Uehara S, Kobayashi Y, Ueha S, Matsushima K, Yamaguchi A, Imai Y, Iimura T.
  • Journal Title: Nat Commun Volume: 8 Issue: 1 Pages: 2226-2226
  • DOI: 10.1038/s41467-017-02368-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Long-Lasting Graft-Derived Donor T Cells Contribute to the Pathogenesis of Chronic Graft-versus-Host Disease in Mice. (2017)
  • Author(s): Kosugi-Kanaya M, Ueha S, Abe J, Shichino S, Shand FHW, Morikawa T, Kurachi M, Shono Y, Sudo N, Yamashita A, Suenaga F, Yokoyama A, Yong W, Imamura M, Teshima T, Matsushima K.
  • Journal Title: Front Immunol Volume: 8 Pages: 1842-1842
  • DOI: 10.3389/fimmu.2017.01842
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comprehensive single-cell transcriptome analysis reveals heterogeneity in endometrioid adenocarcinoma tissues. (2017)
  • Author(s): Hashimoto S, Tabuchi Y, Yurino H, Hirohashi Y, Deshimaru S, Asano T, Mariya T, Oshima K, Takamura Y, Ukita Y, Ametani A, Kondo N, Monma N, Takeda T, Misu S, Okayama T, Ikeo K, Saito T, Kaneko S, Suzuki Y, Hattori M, Matsushima K, et al.
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 14225-14225
  • DOI: 10.1038/s41598-017-14676-3
  • Peer Reviewed / Open Access
• [Journal Article] Combination of anti-CD4 antibody treatment and donor lymphocyte infusion ameliorates graft-versus-host disease while preserving graft-versus-tumor effects in murine allogeneic hematopoietic stem cell transplantation. (2017)
  • Author(s): Ueha S, Yokochi S, Ishiwata Y, Kosugi-Kanaya M, Shono Y, Shibayama S, Ito S, Matsushima K.
  • Journal Title: Cancer Sci Volume: 108 Issue: 10 Pages: 1967-1973
  • DOI: 10.1111/cas.13346
  • Peer Reviewed / Open Access
• [Journal Article] SIV targeting of CXCR3+CD4+ T cells in secondary lymphoid organs associates with robust CXCL10 expression in monocyte/macrophage subsets. (2017)
  • Author(s): Fujino, M., H. Sato, T. Okamura, A. Uda, S. Takeda, N. Ahmed, S. Shichino, T. Shiino, Y. Saito, S. Watanabe, C. Sugimoto, M. Kuroda, M. Ato, Y. Nagai, S. Izumo, K. Matsushima, M. Miyazawa, A. Ansari, F. Villinger, and K. Mori
  • Journal Title: Journal of Virology Volume: 印刷中 Issue: 13
  • DOI: 10.1128/jvi.00439-17
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] マウス肺線維症モデルへの間葉系幹細胞の移入ルートおよびドナーによる移入効率と治療効果の解析 (2018)
  • Author(s): 中島拓弥・七野成之・上羽悟史・松島綱治
  • Organizer: 第39回日本炎症・再生医学会
• [Presentation] マウス肺線維症モデルへの移入ルートおよびドナーによる移入効率と治療効果の解析 (2018)
  • Author(s): 中島拓弥・七野成之・上羽悟史・松島綱治
  • Organizer: 第18回分子予防環境医学研究会大会
• [Presentation] ブレオマイシン誘導マウス肺線維症 モデルにおける経時的１細胞 トランスクリプトーム解析 (2018)
  • Author(s): 七野 成之, 橋本 真一, 上羽 悟志, 松島 綱治
  • Organizer: 第18回分子予防環境医学研究会大会
• [Presentation] 細胞と分子の動きから観る臓器線維化 (2018)
  • Author(s): 七野 成之, 津久井 達也, 橋本 真一, 大辻 幹哉, 上羽 悟史, 稲垣 豊, 島野 仁, 松島 綱治
  • Organizer: 「炎症の慢性化機構の解明と制御に向けた基盤技術の創出」研究開発領域公開シンポジウム
  • Invited
• [Presentation] 炎症の遷延化・不可逆化に伴う臓器線維症の細胞基盤 (2018)
  • Author(s): 松島 綱治
  • Organizer: 第17回分子予防環境医学研究会大会
  • Invited
• [Presentation] 担がんマウスにおけるCD8+ T細胞レパトアの臓器別解析 (2018)
  • Author(s): 七野 成之, 青木 寛泰, 橋本 真一, 荻原 春, 上羽 悟史, 松島 綱治
  • Organizer: 第17回分子予防環境医学研究会大会
• [Presentation] TCR sequencing reveals the generation and expansion of tumor-specific CD8+T cell clones after anti-CD4 antibody treatment in tumor-bearing mice (2018)
  • Author(s): Satoshi Ueha, Aoki Hiroyasu, Shigeyuki Shichino, Ogiwara Haru, Shinichi Hashimoto, Kazuhiro Kakimi, Kouji Matsushima
  • Organizer: Keystone Symposia
  • Int'l Joint Research
• [Presentation] Transcriptome analysis reveals PDGF signaling-dependent regulation of myelofibrosis in murine chronic graft-versus-host diseases (2017)
  • Author(s): Shigeyuki Shichino, Satoshi Ueha, Naoto Sudo, Mizuha Kosugi-Kanaya, Francis HW Shand, Teppei Morikawa, Shin-ichi Hashimoto, Takanori Teshima, Kouji Matsushima
  • Organizer: 5th Annual Meeting of the International Cytokine and Interferon Society
  • Int'l Joint Research
• [Presentation] An organ-wide transcriptome of stromal cells identifies the core signature of steady-state murine fibroblasts (2017)
  • Author(s): Shigeyuki SHICHINO, Satoshi UEHA, Shin-ichi HASHIMOTO, Inagaki YUTAKA, Kouji MATSUSHIMA
  • Organizer: 4th Lymphoid tissue meeting
  • Int'l Joint Research
• [Presentation] 肺線維症における活性化線維芽細胞の起源とその活性化制御機構 (2017)
  • Author(s): 七野 成之, 上羽 悟史, 橋本 真一, 松島 綱治
  • Organizer: 第38回日本炎症・再生医学会
  • Invited
• [Presentation] 慢性GVHDにおける骨髄線維化の分子メカニズムの検討 (2017)
  • Author(s): 七野 成之, 上羽 悟史, 須藤 直人、小杉 瑞葉, 松島 綱治
  • Organizer: 第3回日本骨免疫学会
• [Presentation] An anti-CD4 depleting antibody reverses regulatory T cell-induced suppression of dendritic cells while preventing non-specific CD4+ T cell responses in tumor-bearing mice (2017)
  • Author(s): Satoshi Ueha, Haru Ogiwara, Shoji Yokochi, Yoshiro Ishiwata, Francis Shand, Shohei Hori, Kazuhiro Kakimi, Satoru Ito, Kouji Matsushima
  • Organizer: 36th Sapporo International?Cancer Symposium
  • Int'l Joint Research
• [Presentation] An anti-CD4 depleting antibody reverses regulatory T cell-induced suppression of dendritic cells while preventing non-specific CD4+ T cell responses in tumor-bearing mice (2017)
  • Author(s): Satoshi Ueha, Haru Ogiwara, Shoji Yokochi, Yoshiro Ishiwata, Francis Shand, Shohei Hori, Kazuhiro Kakimi, Satoru Ito, Kouji Matsushima
  • Organizer: AACR Annual Meeting 2017
  • Int'l Joint Research
• [Presentation] Identification of a functional and transcriptional signature for tumor-infiltrating dendritic cells in mouse (2017)
  • Author(s): Satoshi Ueha, Haru Ogiwara, Shigeyuki Shichino, Jun Abe, Francis Shand, Shinichi Hashimoto, Kouji Matsushima
  • Organizer: 5th Annual Meeting of the International Cytokine and Interferon Society
  • Int'l Joint Research
• [Presentation] TCR sequencing reveals the generation and expansion of tumor-specific CD8+T cell clones after anti-CD4 antibody treatment in tumor-bearing mice (2017)
  • Author(s): Satoshi Ueha, Aoki Hiroyasu, Shigeyuki Shichino, Ogiwara Haru, Shinichi Hashimoto, Kazuhiro Kakimi, Kouji Matsushima
  • Organizer: The 46th Japanese Society for Immunology
• [Presentation] TCR sequencing reveals the generation and expansion of tumor-specific CD8+ T cell clones after anti-CD4 antibody treatment in tumor-bearing mice (2017)
  • Author(s): Satoshi Ueha, Yasuhiro Aoki, Shigeyuki Shichino, Haru Ogiwara, Shinichi Hashimoto, Kazuhiro Kakimi, Satoru Ito, Kouji Matsushima
  • Organizer: 第21回日本がん免疫学会総会
• [Presentation] TCR sequencing reveals the generation and expansion of tumor-specific CD8+ T cell clones after anti-CD4 antibody treatment in tumor-bearing mice (2017)
  • Author(s): Satoshi Ueha, Yasuhiro Aoki, Shigeyuki Shichino, Haru Ogiwara, Shinichi Hashimoto, Kazuhiro Kakimi, Satoru Ito, Kouji Matsushima
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] 抗CD4抗体とDLIを併用した同種造血幹細胞移植による低免疫原性固形がん治療の可能性 (2017)
  • Author(s): 上羽 悟史、石渡 義郎、橫地祥司、伊藤哲、松島綱治
  • Organizer: 第26回 日本癌病態治療研究会
• [Presentation] 担がんマウスにおけるCD8+ T細胞レパトアの臓器別解析 (2017)
  • Author(s): 青木 寛泰、七野 成之、橋本 真一、上羽 悟史、松島 綱治
  • Organizer: 第3回日本骨免疫学会