Identification of vascular endothelial stem cells in the eye and their role in diabetic retinopathy and age-related macular degeneration

• Project/Area Number: 16K20317
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Ophthalmology
• Research Institution: Osaka University
• Principal Investigator: Wakabayashi Taku 大阪大学, 医学系研究科, 助教 (20733116)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 血管新生 / 血管内皮細胞 / 幹細胞 / Side population / CD157 / 糖尿病網膜症 / 加齢黄斑変性 / 血管再生 / 血管幹細胞 / 血管内皮幹細胞 / 加齢黄斑変性症

Outline of Final Research Achievements

Diabetic retinopathy (DR) and age-related macular degeneration (AMD) are associated with ischemia and pathological angiogenesis, and are leading cause of blindness worldwide. The purpose of this study was to identify stem cells in the pre-existing blood vessels and to elucidate their relationship with DR and AMD. Based on our research, we have newly reported the following data. (1) Identification of the side population (SP) cells in the vascular endothelial cells in the retina and choroid using DNA-binding dye Hoechst. (2) Identification of CD157 (Bst1) as a molecule that is specifically expressed in vascular endothelial SP cells (Cell Stem Cell 2018), (3) CD157-positive vascular endothelial cells are mainly located in veins and contribute to the turnover of blood vessels by initiating angiogenesis as stem cells in the blood vessels. We would like to further progress this research for the development of new therapeutic methods targeting CD157-positive vascular endothelial stem cells.

Academic Significance and Societal Importance of the Research Achievements

糖尿病網膜症や加齢黄斑変性症は中途失明に関わる病気であり、現行治療（レーザー、抗VEGF薬、手術）でも病勢を抑えられない場合がある。このため新たな治療法開発を目指す意義がある。
我々は目の網膜血管や脈絡膜血管に存在する幹細胞を今回はじめて発見した。この幹細胞は、毛細血管のターンオーバーにかかわっていることがわかった。糖尿病網膜症や加齢黄斑変性では、網膜や脈絡膜の毛細血管が障害され、病的血管新生が生じて視力が低下する。幹細胞が目の毛細血管を維持する機能を維持できれば、糖尿病網膜症や加齢黄斑変性に対してこれまでと異なる視点で新たな治療法を開発できる可能性があるため、今後もさらに研究を進めていきたい。

Research Products

• [Journal Article] Isolation of tissue-resident vascular endothelial stem cells from mouse liver (2020)
  • Author(s): Naito Hisamichi、Wakabayashi Taku、Ishida Masako、Gil Chang-Hyun、Iba Tomohiro、Rahmawati Fitriana Nur、Shimizu Shota、Yoder Mervin C.、Takakura Nobuyuki
  • Journal Title: Nature Protocols Volume: 15 Issue: 3 Pages: 1066-1081
  • DOI: 10.1038/s41596-019-0276-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effect of Gas Tamponade on the Intraocular Lens Position and Refractive Error After Phacovitrectomy: A Swept-Source Anterior Segment OCT Analysis (2020)
  • Author(s): Shiraki N, Wakabayashi T, Sakaguchi H, Nishida K.
  • Journal Title: Ophthalmology Volume: 127 Issue: 4 Pages: 511-515
  • DOI: 10.1016/j.ophtha.2019.10.021
  • Peer Reviewed
• [Journal Article] Tachyphylaxis during treatment of exudative age-related macular degeneration with aflibercept. (2019)
  • Author(s): Hara C, Wakabayashi T, Fukushima Y, Sayanagi K, Kawasaki R, Sato S, Sakaguchi H, Nishida K.
  • Journal Title: Graefes Arch Clin Exp Ophthalmol. Volume: 257 Issue: 11 Pages: 2559-2569
  • DOI: 10.1007/s00417-019-04456-2
  • Peer Reviewed
• [Journal Article] Isolation of tissue-resident endothelial stem cells and their use in regenerative medicine (2019)
  • Author(s): Iba Tomohiro、Naito Hisamichi、Shimizu Shota、Rahmawati Fitriana Nur、Wakabayashi Taku、Takakura Nobuyuki
  • Journal Title: Inflammation and Regeneration Volume: 39 Issue: 1 Pages: 9-9
  • DOI: 10.1186/s41232-019-0098-9
  • NAID: 120007096900
  • Peer Reviewed / Open Access
• [Journal Article] Observation of Treated Iris Neovascularization by Swept-Source-Based En-Face Anterior-Segment Optical Coherence Tomography Angiography (2019)
  • Author(s): Shiozaki D, Sakimoto S, Shiraki A, Wakabayashi T, Fukushima Y, Oie Y, Usui S, Sato S, Sakaguchi H, Nishida K.
  • Journal Title: Sci Rep . Volume: 9 Issue: 1 Pages: 10262-10262
  • DOI: 10.1038/s41598-019-46514-z
  • Peer Reviewed / Open Access
• [Journal Article] Evaluation of Retinal Nonperfusion in Branch Retinal Vein Occlusion Using Wide-Field Optical Coherence Tomography Angiography (2019)
  • Author(s): Shiraki A, Sakimoto S, Tsuboi K, Wakabayashi T, Hara C, Fukushima Y, Sayanagi K, Nishida K, Sakaguchi H, Nishida K.
  • Journal Title: Acta Ophthalmol . Volume: 97 Issue: 6 Pages: 913-918
  • DOI: 10.1111/aos.14087
  • Peer Reviewed
• [Journal Article] Effect of intravitreal injection of aflibercept or ranibizumab on chorioretinal atrophy in myopic choroidal neovascularization. (2019)
  • Author(s): Sayanagi K, Uematsu S, Hara C, Wakabayashi T, Fukushima Y, Sato S, Ikuno Y, Nishida K.
  • Journal Title: Graefes Arch Clin Exp Ophthalmol. Volume: 257 Issue: 4 Pages: 749-957
  • DOI: 10.1007/s00417-018-04214-w
  • Peer Reviewed
• [Journal Article] Anterior segment Scheimpflug imaging for detecting primary angle closure disease. (2019)
  • Author(s): Winegarner A, Miki A, Kumoi M, Ishida Y, Wakabayashi T, Sakimoto S, Usui S, Matsushita K, Nishida K.
  • Journal Title: Graefes Arch Clin Exp Ophthalmol. Volume: 257 Issue: 1 Pages: 161-167
  • DOI: 10.1007/s00417-018-4171-x
  • Peer Reviewed
• [Journal Article] Retinal Microvasculature and Visual Acuity after Intravitreal Aflibercept in Diabetic Macular Edema: An Optical Coherence Tomography Angiography Study. (2019)
  • Author(s): Busch C, Wakabayashi T, Sato T, Fukushima Y, Hara C, Shiraki N, Winegarner A, Nishida K, Sakaguchi H, Nishida K.
  • Journal Title: Sci Rep. Volume: 9 Issue: 1 Pages: 1561-1561
  • DOI: 10.1038/s41598-018-38248-1
  • Peer Reviewed / Open Access
• [Journal Article] Purtscher-like Retinopathy Associated with Systemic Lupus Erythematosus Observed Using Wide-field OCT Angiography. (2019)
  • Author(s): Ishibashi T, Wakabayashi T, Nishida K.
  • Journal Title: Ophthalmol Retina. Volume: 3 Issue: 1 Pages: 76-76
  • DOI: 10.1016/j.oret.2018.07.015
  • Peer Reviewed
• [Journal Article] Changes in Retinal Microvasculature and Visual Acuity After Antivascular Endothelial Growth Factor Therapy in Retinal Vein Occlusion. (2018)
  • Author(s): Winegarner A, Wakabayashi T, Fukushima Y, Sato T, Hara-Ueno C, Busch C, Nishiyama I, Shiraki N, Sayanagi K, Nishida K, Sakaguchi H, Nishida K.
  • Journal Title: Invest Ophthalmol Vis Sci Volume: 59 Issue: 7 Pages: 2708-2716
  • DOI: 10.1167/iovs.17-23437
  • Peer Reviewed
• [Journal Article] Optical Biometry-Based Intraocular Lens Calculation and Refractive Outcomes after Phacovitrectomy for Rhegmatogenous Retinal Detachment and Epiretinal Membrane. (2018)
  • Author(s): Shiraki N, Wakabayashi T, Sakaguchi H, Nishida K.
  • Journal Title: Sci Rep. Volume: 8 Issue: 1 Pages: 11319-11319
  • DOI: 10.1038/s41598-018-29553-w
  • Peer Reviewed / Open Access
• [Journal Article] High-Temperature Requirement A 1 Causes Photoreceptor Cell Death in Zebrafish Disease Models (2018)
  • Author(s): Oura Yoshihito、Nakamura Machiko、Takigawa Tohru、Fukushima Yoko、Wakabayashi Taku、Tsujikawa Motokazu、Nishida Kohji
  • Journal Title: The American Journal of Pathology Volume: 188 Issue: 12 Pages: 2729-2744
  • DOI: 10.1016/j.ajpath.2018.08.012
  • Peer Reviewed
• [Journal Article] LPA4-Mediated Vascular Network Formation Increases the Efficacy of Anti-PD-1 Therapy against Brain Tumors (2018)
  • Author(s): Eino Daisuke、Tsukada Yohei、Naito Hisamichi、Kanemura Yonehiro、Iba Tomohiro、Wakabayashi Taku、Muramatsu Fumitaka、Kidoya Hiroyasu、Arita Hideyuki、Kagawa Naoki、Fujimoto Yasunori、Takara Kazuhiro、Kishima Haruhiko、Takakura Nobuyuki
  • Journal Title: Cancer Research Volume: 78 Issue: 23 Pages: 6607-6620
  • DOI: 10.1158/0008-5472.can-18-0498
  • Peer Reviewed / Open Access
• [Journal Article] TAK1 Prevents Endothelial Apoptosis and Maintains Vascular Integrity. (2018)
  • Author(s): Naito H, Iba T, Wakabayashi T, Tai-Nagara I, Suehiro JI, Jia W, Eino D, Sakimoto S, Muramatsu F, Kidoya H, Sakurai H, Satoh T, Akira S, Kubota Y, Takakura N.
  • Journal Title: Dev Cell. Volume: 48 Issue: 2 Pages: 151-166
  • DOI: 10.1016/j.devcel.2018.12.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CD157 Marks Tissue-Resident Endothelial Stem Cells with Homeostatic and Regenerative Properties. (2018)
  • Author(s): Wakabayashi T, Naito H, Suehiro JI, Lin Y, Kawaji H, Iba T, Kouno T, Ishikawa-Kato S, Furuno M, Takara K, Muramatsu F, Weizhen J, Kidoya H, Ishihara K, Hayashizaki Y, Nishida K, Yoder MC, Takakura N.
  • Journal Title: Cell Stem Cell. Volume: 22 Issue: 3 Pages: 348-397
  • DOI: 10.1016/j.stem.2018.01.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Long-term Reconstruction of Foveal Microstructure and Visual Acuity After Idiopathic Macular Hole Repair: Three-year Follow-up Study. (2018)
  • Author(s): Kitao M, Wakabayashi T, Nishida K, Sakaguchi H, Nishida K.
  • Journal Title: British Journal of Ophthalmology Volume: - Issue: 2 Pages: 238-244
  • DOI: 10.1136/bjophthalmol-2017-311689
  • Peer Reviewed
• [Journal Article] Inverted Internal limiting Membrane Insertion versus Standard Internal Limiting Membrane Peeling for Macular Hole Retinal Detachment in High Myopia: One-Year Study. (2018)
  • Author(s): Wakabayashi T, Ikuno Y, Shiraki N, Matsumura N, Sakaguchi H, Nishida K.
  • Journal Title: Graefes Arch Clin Exp Ophthalmol Volume: -
  • Peer Reviewed
• [Journal Article] Retinal Microvasculature and Visual Acuity after Intravitreal Aflibercept in Eyes with Central Retinal Vein Occlusion: An Optical Coherence Tomography Angiography Study. (2017)
  • Author(s): Winegarner A, Wakabayashi T, Hara-Ueno C, Sato T, Busch C, Fukushima Y, Sayanagi K, Nishida K, Sakaguchi H, Nishida K.
  • Journal Title: Retina Volume: - Issue: 10 Pages: 2067-2072
  • DOI: 10.1097/iae.0000000000001828
  • Peer Reviewed
• [Journal Article] Intraoperative B-scan ultrasonography and pars plana vitrectomy for severe open globe injury with hemorrhagic retinal and choroidal detachment. (2017)
  • Author(s): Shiraki N, Wakabayashi T, Sato T, Sakaguchi H, Nishida K.
  • Journal Title: Graefes Arch Clin Exp Ophthalmol Volume: 225 Issue: 11 Pages: 2287-2291
  • DOI: 10.1007/s00417-017-3771-1
  • Peer Reviewed
• [Journal Article] Lysophosphatidic acid receptor 4 activation augments drug delivery in tumors by tightening endothelial cell-cell contact. (2017)
  • Author(s): Takara K., Eino D., Ando K., Yasuda D., Naito H., Tsukada Y., Iba T., Wakabayashi T., Muramatsu F., Kidoya H., Fukuhara S., Mochizuki N., Ishii S., Kishima H., Takakura N.
  • Journal Title: Cell Reports Volume: 20 Issue: 9 Pages: 2072-2086
  • DOI: 10.1016/j.celrep.2017.07.080
  • Peer Reviewed / Open Access
• [Journal Article] Retinal thickness in parafoveal subfields and visual acuity after vitrectomy for macula-off rhegmatogenous retinal detachment repair. (2017)
  • Author(s): Sato T, Wakabayashi T, Shiraki N, Sakaguchi H.
  • Journal Title: Graefes Arch Clin Exp Ophthalmol Volume: 255 Issue: 9 Pages: 1737-1742
  • DOI: 10.1007/s00417-017-3716-8
  • Peer Reviewed
• [Journal Article] Retinal Microvasculature and Visual Acuity in Eyes With Branch Retinal Vein Occlusion: Imaging Analysis by Optical Coherence Tomography Angiography. (2017)
  • Author(s): Wakabayashi T, Sato T, Hara-Ueno C, Fukushima Y, Sayanagi K, Shiraki N, Sawa M, Ikuno Y, Sakaguchi H, Nishida K.
  • Journal Title: Invest Ophthalmol Vis Sci Volume: 58 Issue: 4 Pages: 2087-2094
  • DOI: 10.1167/iovs.16-21208
  • Peer Reviewed
• [Presentation] 血管新生の新規分子機構の解明と虚血性眼疾患の治療法開発． (2019)
  • Author(s): 若林卓
  • Organizer: 第123回日本眼科学会総会．第24回ROHTO AWARD受賞記念講演会
  • Invited
• [Presentation] Retinal microvasculature and visual acuity in branch retinal vein occlusion. (2019)
  • Author(s): 若林卓
  • Organizer: The international Crosstalk Symposium by Young Ophthalmologists.第123回日本眼科学会総会．
• [Presentation] 視機能Upを目指した網膜硝子体疾患の外科的治療戦略． (2019)
  • Author(s): 若林卓
  • Organizer: 第29回愛知眼科フォーラム
• [Presentation] Identification of resident vasculoreparative endothelial stem cells responsible for ocular angiogenesis. (2018)
  • Author(s): Wakabayashi T, Naito H, Takakura N, Nishida K.
  • Organizer: The Association for Research in Vision and Ophthalmology, Annual Meeting.
  • Int'l Joint Research
• [Presentation] 血管再生は可能？血管における幹細胞研究最前線． (2018)
  • Author(s): 若林卓
  • Organizer: 日本臨床眼科学会
• [Presentation] 近視性網膜分離症に対するFovea sparing ILM peelingの手術成績． (2018)
  • Author(s): 若林卓、白木暢彦、佐柳香織、石橋朋幸、坂口裕和、生野恭司、西田幸二．
  • Organizer: 第2回日本近視学会総会
• [Presentation] 広角OCT angiographyによる増殖糖尿病網膜症の網膜新生血管検出率． (2018)
  • Author(s): 白木彰彦、若林卓、原千佳子、福嶋葉子、崎元晋、大浦嘉仁、西田健太郎、佐藤茂、川崎良、坂口裕和、西田幸二．
  • Organizer: 第72回日本臨床眼科学会
• [Presentation] Vascular endothelial stem cell system in vascular regeneration and maintenance. (2017)
  • Author(s): Wakabayashi T, Naito H, Takakura N.
  • Organizer: Keystone Symposia Conference
  • Int'l Joint Research
• [Presentation] Endothelial TAK1 inhibits EC apoptosis. (2017)
  • Author(s): Naito H, Wakabayashi T, Takakura N.
  • Organizer: Keystone Symposia Conference
  • Int'l Joint Research
• [Presentation] Simulation of Panretinal Laser Photocoagulation Using Optical Analysis Software. (2017)
  • Author(s): Nishida K, Sakaguchi H, Wakabayashi T, Nishida K
  • Organizer: The American Society of Retina Specialists
  • Int'l Joint Research
• [Presentation] Intraoperative B-scan Ultrasonography and Pars Plana Vitrectomy for Severe Open Globe Injury. (2017)
  • Author(s): Wakabayashi T, Shiraki N, Sakaguchi H, Nishida K
  • Organizer: The American Society of Retina Specialists
  • Int'l Joint Research
• [Presentation] Quantitative Retinal Capillary Density Evaluated by OCT Angiography and Visual Acuity in Eyes With Resolved Branch Retinal Vein Occlusion. (2016)
  • Author(s): Sato T, Wakabayashi T, Sayanagi K, Fukushima Y, Shiraki N, Hara C, Sakaguchi H.
  • Organizer: American Academy of Ophthalmology
  • Place of Presentation: Chicago
  • Year and Date: 2016-10-16
• [Presentation] Inverted ILM insertion vs Standard ILM peeling for macular hole retinal detachment in high myopia. (2016)
  • Author(s): Wakabayashi T.
  • Organizer: 3rd International conference on Pathologic Myopia.
  • Place of Presentation: Tokyo
  • Year and Date: 2016-10-01
• [Presentation] Retinal microvascular changes in branch retinal vein occlusion evaluated by OCT angiography after intravitreal anti-VEGF therapy: 12-month results. (2016)
  • Author(s): Wakabayashi T, Nishida K, Sakaguchi H, Nishida K.
  • Organizer: The American Society of Retina Specialists
  • Place of Presentation: San Francisco
  • Year and Date: 2016-08-11