Cellular and molecular mechanisms underlying inflammation and fibrosis in pericyte-deficient retinai

• Project/Area Number: 19H03437
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Nagoya City University
• Principal Investigator: Uemura Akiyoshi 名古屋市立大学, 医薬学総合研究院(医学), 教授 (30373278)
• Co-Investigator(Kenkyū-buntansha): 西山 功一 熊本大学, 国際先端医学研究機構, 准教授 (80398221)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2021: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2020: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2019: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
• Keywords: 網膜 / 炎症 / 線維化 / ペリサイト / ミクログリア / マクロファージ

Outline of Research at the Start

糖尿病網膜症では、血管壁におけるペリサイトの消失がバリア機能を破綻させ、炎症と線維化が進行する。しかし、高血糖モデル動物ではヒト網膜症を再現できないため、個々の病態の因果関係については不明な点が多い。そこで我々は、抗PDGFRβ抗体を投与してペリサイトを消失させることにより、高血糖を経ずに糖尿病網膜症と同様の病態を再現するモデルマウスを確立した。本研究では、ペリサイト消失網膜における炎症と線維化の細胞・分子機構を解明することにより、糖尿病網膜症を含む眼疾患の新規治療法開発に展開することをめざす。

Outline of Final Research Achievements

By intraperitoneally injecting an anti-PDGFRβ monoclonal antibody (clone APB5) to neonatal mice, we previously established a pericyte-deficient retinopathy model, which reproduced retinal vascular disorders characteristic to diabetic retinopathy. In the present study, we elucidated that mononuclear phagocytes infiltrating around the pericyte-free retinal vessels were derived from both activated microglia and monocyte-derived macrophages. After the onset of retinal detachment caused by the hyperpermeability of the pericyte-free retinal vessels, activated microglia accumulated in the subretinal spaces and induced fibrosis. In these fibrotic tissues, myofibroblasts were derived both pericytes and retinal pigment epithelium cells.

Academic Significance and Societal Importance of the Research Achievements

糖尿病網膜症では、血管壁におけるペリサイト消失によりバリア機能が破綻する。こうした状況では炎症性サイトカインの発現が上昇し、単核食細胞が網膜内に浸潤する。さらに進行した網膜症では、線維血管増殖膜が牽引性網膜剥離をきたして失明に至る。しかし、高血糖モデル動物ではこれらの病態を十分に再現できないため、網膜における炎症と線維化の細胞・分子機構については不明な点が多い。本研究ではペリサイト消失網膜において炎症と線維化を再現し、単核食細胞や筋線維芽細胞の由来を同定することに成功した。本研究の成果は、糖尿病網膜症の病態理解を深め、新規治療標的の探索に資すると期待される。

Research Products

• [Journal Article] Multimodal evaluation of an interphotoreceptor retinoid- binding protein-induced mouse model of experimental autoimmune uveitis (2022)
  • Author(s): Yang JM, Yun K, Jeon J, Yang HY, Kim B, Jeong S, Lee J, Oh WY, Uemura A, Song JS, Kim P, Lee JY.
  • Journal Title: Exp Mol Med Volume: 54 Issue: 3 Pages: 252-262
  • DOI: 10.1038/s12276-022-00733-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Embryonic Pericytes Promote Microglial Homeostasis and Their Effects on Neural Progenitors in the Developing Cerebral Cortex (2022)
  • Author(s): Hattori Y, Itoh H, Tsugawa Y, Nishida Y, Kurata K, Uemura A, Miyata T
  • Journal Title: The Journal of Neuroscience Volume: 42 Issue: 3 Pages: 362-376
  • DOI: 10.1523/jneurosci.1201-21.2021
  • Peer Reviewed / Open Access
• [Journal Article] Quantitative modeling of regular retinal microglia distribution. (2021)
  • Author(s): Endo Y, Asanuma D, Namiki S, Sugihara K, Hirose K, Uemura A, Kubota Y, Miura T.
  • Journal Title: Sci Rep Volume: 11 Issue: 1 Pages: 22671-22671
  • DOI: 10.1038/s41598-021-01820-3
  • Peer Reviewed / Open Access
• [Journal Article] VEGFR1 signaling in retinal angiogenesis and microinflammation (2021)
  • Author(s): Uemura A, Fruttiger M, D'Amore PA, De Falco S, Joussen AM, Sennlaub F, Brunck LR, Johnson KT, Lambrou GN, Rittenhouse KD, Langmann T.
  • Journal Title: Prog Retin Eye Res Volume: 84 Pages: 100954-100954
  • DOI: 10.1016/j.preteyeres.2021.100954
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Semaphorin3E-PlexinD1 signaling in coronary artery and lymphatic vessel development with clinical implications in myocardial recovery (2021)
  • Author(s): Maruyama Kazuaki、Naemura Kazuaki、Arima Yuichiro、Uchijima Yasunobu、Nagao Hiroaki、Yoshihara Kenji、Singh Manvendra K.、Uemura Akiyoshi、Matsuzaki Fumio、Yoshida Yutaka、Kurihara Yukiko、Miyagawa-Tomita Sachiko、Kurihara Hiroki
  • Journal Title: iScience Volume: 24 Issue: 4 Pages: 102305-102305
  • DOI: 10.1016/j.isci.2021.102305
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Rho GTPases in Retinal Vascular Diseases (2021)
  • Author(s): Uemura Akiyoshi、Fukushima Yoko
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 7 Pages: 3684-3684
  • DOI: 10.3390/ijms22073684
  • Peer Reviewed / Open Access
• [Journal Article] RhoJ Regulates α5β1 Integrin Trafficking to Control Fibronectin Remodeling during Angiogenesis (2020)
  • Author(s): Sundararaman Ananthalakshmy、Fukushima Yoko、Norman Jim C.、Uemura Akiyoshi、Mellor Harry
  • Journal Title: Current Biology Volume: 30 Issue: 11 Pages: 2146-2155.e5
  • DOI: 10.1016/j.cub.2020.03.042
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] RhoJ integrates attractive and repulsive cues in directional migration of endothelial cells. (2020)
  • Author(s): Fukushima Y., Nishiyama K., Kataoka H., Fruttiger M. Fukuhara S., Nishida K., Mochizuki N., Kurihara H., Nishikawa S., Uemura A.
  • Journal Title: EMBO J. Volume: 39 Issue: 12
  • DOI: 10.15252/embj.2019102930
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Loss of Down Syndrome Critical Region-1 Mediated-Hypercholesterolemia Accelerates Corneal Opacity Via Pathological Neovessel Formation (2020)
  • Author(s): Muramatsu Masashi、Nakagawa Suguru、Osawa Tsuyoshi、Toyono Tetsuya、Uemura Akiyoshi、Kidoya Hiroyasu、Takakura Nobuyuki、Usui Tomohiko、Ryeom Sandra、Minami Takashi
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology Volume: 40 Issue: 10 Pages: 2425-2439
  • DOI: 10.1161/atvbaha.120.315003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Remodeling mechanisms determine size distributions in developing retinal vasculature (2020)
  • Author(s): Iizuka Osamu、Kawamura Shotaro、Tero Atsushi、Uemura Akiyoshi、Miura Takashi
  • Journal Title: PLOS ONE Volume: 15 Issue: 10 Pages: e0235373-e0235373
  • DOI: 10.1371/journal.pone.0235373
  • Peer Reviewed / Open Access
• [Journal Article] A new perfusion culture method with a self-organized capillary network (2020)
  • Author(s): Sugihara Kei、Yamaguchi Yoshimi、Usui Shiori、Nashimoto Yuji、Hanada Sanshiro、Kiyokawa Etsuko、Uemura Akiyoshi、Yokokawa Ryuji、Nishiyama Koichi、Miura Takashi
  • Journal Title: PLOS ONE Volume: 15 Issue: 10 Pages: e0240552-e0240552
  • DOI: 10.1371/journal.pone.0240552
  • NAID: 120006993986
  • Peer Reviewed / Open Access
• [Journal Article] Dll4 Suppresses Transcytosis for Arterial Blood-Retinal Barrier Homeostasis. (2020)
  • Author(s): Yang JM, Park CS, Kim SH, Noh TW, Kim JH, Park S, Lee J, Park JR, Yoo D, Jung HH, Takase H, Shima DT, Schwaninger M, Lee S, Kim IK, Lee J, Ji YS, Jon S, Oh WY, Kim P, Uemura A, Ju YS, Kim I.
  • Journal Title: Circ Res Volume: 126 Issue: 6 Pages: 767-783
  • DOI: 10.1161/circresaha.119.316476
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Mechanisms of endothelial cell coverage by pericytes: computational modelling of cell wrapping and in vitro experiments. (2020)
  • Author(s): Sugihara K, Sasaki S, Uemura A, Kidoaki S, Miura T.
  • Journal Title: J R Soc Interface Volume: 17 Issue: 162 Pages: 20190739-20190739
  • DOI: 10.1098/rsif.2019.0739
  • Peer Reviewed / Open Access
• [Journal Article] Ursodeoxycholic Acid Attenuates the Retinal Vascular Abnormalities in Anti-PDGFR-β Antibody-Induced Pericyte Depletion Mouse Models. (2020)
  • Author(s): Shiraya T, Araki F, Ueta T, Fukunaga H, Totsuka K, Arai T, Uemura A, Moriya K, Kato S.
  • Journal Title: Sci Rep Volume: 10 Issue: 1 Pages: 977-977
  • DOI: 10.1038/s41598-020-58039-x
  • Peer Reviewed / Open Access
• [Journal Article] Semaphorin 3E/PlexinD1 signaling is required for cardiac ventricular compaction. (2019)
  • Author(s): Sandireddy R, Cibi DM, Gupta P, Singh A, Tee N, Uemura A, Epstein JA, Singh MK.
  • Journal Title: JCI Insight Volume: 4 Issue: 16 Pages: 125908-125908
  • DOI: 10.1172/jci.insight.125908
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 活性化ミクログリアはペリサイト消失網膜の線維化を促進する (2020)
  • Author(s): 植村明嘉
  • Organizer: 第43回日本分子生物学会年会
• [Presentation] Activated microglia promote fibrosis in pericyte-deficient retina (2020)
  • Author(s): Komine Y, Ikeda W, Inoue N, Kurata K, Ogasawara H, Goto S, Onishi A, Kurihara H, Imai T, Uemura A
  • Organizer: Keystone Symposium "Fibrosis and Tissue Repair: From Molecules and Mechanics to Therapeutic Approaches"
  • Int'l Joint Research
• [Presentation] Pericyte deficiency sequentially induces inflammation, barrier breakdown, and fibrosis in retina (2019)
  • Author(s): Uemura A, Komine Y, Inoue N, Kurata K, Ikeda W, Ogasawara H, Nishioka E, Nishiyama K, Kurihara H, Imai T
  • Organizer: Asia Australia Vascular Biology Meeting
  • Int'l Joint Research
• [Presentation] 網膜血管障害における炎症と線維化 (2019)
  • Author(s): 植村明嘉
  • Organizer: 第123回日本眼科学会総会
  • Invited
• [Presentation] マクロファージを標的とした糖尿病網膜症の抗体医薬開発 (2019)
  • Author(s): 植村明嘉、池田わたる、西山功一、今井俊夫
  • Organizer: 第62回日本糖尿病学会年次学術集会
  • Invited
• [Presentation] ペリサイト消失網膜における炎症と線維化 (2019)
  • Author(s): 植村明嘉
  • Organizer: 第42回日本分子生物学会年会
  • Invited