Dynamics of epithelial stem cells upon wounding

• Project/Area Number: 17K16317
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Dermatology
• Research Institution: Hokkaido University
• Principal Investigator: Natsuga Ken 北海道大学, 大学病院, 講師 (70645457)
• Research Collaborator: Watanabe Mika ; Fujimura Yu
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 創傷治癒 / 表皮 / 毛包 / 幹細胞 / 再生医学

Outline of Final Research Achievements

In wounds in which the epidermis was selectively removed, there was 1 -3 reepithelialization at 24 hours after wounding as visible through HE staining. The basal layer of the epidermis expressing α6 integrin was present at this point, and cells in the re-epithelialized layer were stained with pan-cytokeratin. Loricrin staining, showing differentiation into epidermal granular layer, was not seen 48 hours after wound creation but was confirmed 72 hours later. HE staining also shows no granular layer at 48 hours after wounding, but at 72 hours after wounding, the final reepithelialization is complete. Lineage tracing also revealed that daughter cells of hair follicle upper stem cells are involved in wound reepithelialization.

Academic Significance and Societal Importance of the Research Achievements

創傷は、病原体の繁殖に伴い感染母地となるとともに、皮膚癌の発生基点ともなりうることから、人類の健康維持において制御すべき非常に重要な疾患である。本研究で確立した実験系は、実験動物を使いつつ、再現性のある表皮選択的除去が可能であり、新しい創傷実験である。この方法をlinage tracingや薬物投与実験と組み合わせることで、上皮創傷の治癒促進因子を探索することが可能となる。特に、転倒の頻度が高い高齢者の皮膚創傷や、自己免疫性・遺伝性水疱性疾患などの患者に対する治療法開発へとつなげることができる。

Research Products

• [Int'l Joint Research] トリノ大学(イタリア)
• [Int'l Joint Research] キングズカレッジロンドン(英国)
• [Int'l Joint Research] トリノ大学(イタリア)
• [Int'l Joint Research]
• [Journal Article] Mutant Lef1 controls Gata6 in sebaceous gland development and cancer (2019)
  • Author(s): Oules Benedicte、Rognoni Emanuel、Hoste Esther、Goss Georgina、Fiehler Ryan、Natsuga Ken、Quist Sven、Mentink Remco、Donati Giacomo、Watt Fiona M
  • Journal Title: The EMBO Journal Volume: 印刷中 Issue: 9
  • DOI: 10.15252/embj.2018100526
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fc-binding proteins enhance autoantibody-induced BP180 depletion in pemphigoid (2019)
  • Author(s): Iwata H, Kamaguchi M, Ujiie H, Ujiie I, Natsuga K, Nishie W, ShimizuH:
  • Journal Title: J Pathol Volume: 247 Issue: 3 Pages: 371-380
  • DOI: 10.1002/path.5196
  • Peer Reviewed
• [Journal Article] Bullous Pemphigoid IgG Induces Cell Dysfunction and Enhances the Motility of Epidermal Keratinocytes via Rac1/Proteasome Activation (2019)
  • Author(s): Tie Duerna、Da Xia、Natsuga Ken、Yamada Nanako、Yamamoto Osamu、Morita Eishin
  • Journal Title: Frontiers in Immunology Volume: 10 Pages: 200-200
  • DOI: 10.3389/fimmu.2019.00200
  • NAID: 120007002182
  • Peer Reviewed / Open Access
• [Journal Article] The direct binding of collagen XVII and collagen IV is disrupted by pemphigoid autoantibodies (2018)
  • Author(s): Kamaguchi Mayumi、Iwata Hiroaki、Nishie Wataru、Toyonaga Ellen、Ujiie Hideyuki、Natsuga Ken、Kitagawa Yoshimasa、Shimizu Hiroshi
  • Journal Title: Laboratory Investigation Volume: 99 Issue: 1 Pages: 48-57
  • DOI: 10.1038/s41374-018-0113-9
  • Peer Reviewed
• [Journal Article] Regulatory T-cell dysfunction induces autoantibodies to bullous pemphigoid antigens in mice and human subjects (2018)
  • Author(s): Muramatsu Ken、Ujiie Hideyuki、Kobayashi Ichiro、Nishie Wataru、Izumi Kentaro、Ito Takamasa、Yoshimoto Norihiro、Natsuga Ken、Iwata Hiroaki、Shimizu Hiroshi
  • Journal Title: Journal of Allergy and Clinical Immunology Volume: 142 Issue: 6 Pages: 1818-1830.e6
  • DOI: 10.1016/j.jaci.2018.03.014
  • Peer Reviewed
• [Journal Article] Novel COL7A1 mutation in a family with bullous dermolysis of the newborn: Phenotypic variability associated with a COL7A1 mutation within the same family (2018)
  • Author(s): Takashima Shota、Shinkuma Satoru、Fujita Yasuyuki、Natsuga Ken、Nomura Toshifumi、Hida Tokimasa、Ishikawa Shuku、Nakamura Hideki、Abe Riichiro、Shimizu Hiroshi
  • Journal Title: The Journal of Dermatology Volume: 印刷中 Issue: 9
  • DOI: 10.1111/1346-8138.14287
  • Peer Reviewed
• [Journal Article] High Expression of Collagen XVII Compensates for Its Depletion Induced by Pemphigoid IgG in the Oral Mucosa. (2018)
  • Author(s): Kamaguchi M, Iwata H, Ujiie H, Natsuga K, Nishie W, Kitagawa Y, Shimizu H.
  • Journal Title: J Invest Dermatol. Volume: - Issue: 8 Pages: 1707-1715
  • DOI: 10.1016/j.jid.2018.03.002
  • Peer Reviewed
• [Journal Article] Intravenous IgG Reduces Pathogenic Autoantibodies, Serum IL-6 Levels, and Disease Severity in Experimental Bullous Pemphigoid Models (2018)
  • Author(s): Sasaoka Tetsumasa、Ujiie Hideyuki、Nishie Wataru、Iwata Hiroaki、Ishikawa Makoto、Higashino Hiroshi、Natsuga Ken、Shinkuma Satoru、Shimizu Hiroshi
  • Journal Title: Journal of Investigative Dermatology Volume: 138 Issue: 6 Pages: 1260-1267
  • DOI: 10.1016/j.jid.2018.01.005
  • NAID: 120006636167
  • Peer Reviewed
• [Journal Article] Epidermal aspects of type VII collagen: Implications for dystrophic epidermolysis bullosa and epidermolysis bullosa acquisita (2018)
  • Author(s): Watanabe Mika、Natsuga Ken、Shinkuma Satoru、Shimizu Hiroshi
  • Journal Title: The Journal of Dermatology Volume: 45 Issue: 5 Pages: 515-521
  • DOI: 10.1111/1346-8138.14222
  • Peer Reviewed
• [Journal Article] Oral mucosa is a useful substrate for detecting autoantibodies of mucous membrane pemphigoid. (2018)
  • Author(s): Kamaguchi M, Iwata H, Ujiie H, Izumi K, Natsuga K, Nishie W, Asaka T, Kitagawa Y, Shimizu H.
  • Journal Title: Br J Dermatol. Volume: 178 Issue: 2 Pages: e119-e121
  • DOI: 10.1111/bjd.15925
  • Peer Reviewed
• [Journal Article] Life before and beyond blistering: The role of collagen XVII in epidermal physiology (2018)
  • Author(s): Natsuga K, Watanabe M, Nishie W, Shimizu H
  • Journal Title: Exp Dermatol Volume: 印刷中 Issue: 10 Pages: 1135-1141
  • DOI: 10.1111/exd.13550
  • Peer Reviewed
• [Journal Article] Acute vascular reaction due to lipo-prostaglandin E1 (2018)
  • Author(s): Fujimura Y, Watanabe M, Natsuga K, Shimizu H
  • Journal Title: J Eur Acad Dermatol Venereol Volume: 印刷中 Issue: 7
  • DOI: 10.1111/jdv.14807
  • Peer Reviewed
• [Journal Article] Sweet's Syndrome Mimicking Anti-Neutrophil Cytoplasmic Antibodies-Associated Vasculitis (2018)
  • Author(s): Kosumi H, Watanabe M, Natsuga K, Miyauchi T, Shiiya C, Ujiie H, Shimizu H
  • Journal Title: Am J Med Volume: 印刷中 Issue: 6 Pages: e241-e242
  • DOI: 10.1016/j.amjmed.2017.12.033
  • Peer Reviewed
• [Journal Article] Portable negative-pressure wound therapy for pyoderma gangrenosum: Report of two cases (2018)
  • Author(s): Yamaguchi Y, Yanagi T, Sato K, Yoshimoto N, Hirata Y, Ujiie I, Nishimura M, Natsuga K, Shiiya C, Tsukinaga I, Shimizu H
  • Journal Title: J Dermatol Volume: 印刷中 Issue: 4 Pages: 483-486
  • DOI: 10.1111/1346-8138.14180
  • NAID: 120006600950
  • Peer Reviewed
• [Journal Article] Extensive Eruptive Syringoma After Liver Transplantation (2018)
  • Author(s): Maeda T、Natsuga K、Nishie W、Yamashita K、Shimizu H
  • Journal Title: Acta Derm Venereol Volume: 98 Issue: 1 Pages: 119-120
  • DOI: 10.2340/00015555-2814
  • Peer Reviewed / Open Access
• [Journal Article] Loss of interaction between plectin and type XVII collagen results in epidermolysis bullosa simplex (2017)
  • Author(s): Natsuga K, Nishie W, Nishimura M, Shinkuma S, Watanabe M, Izumi K, Nakamura H, Hirako Y, Shimizu H
  • Journal Title: Hum Mutat Volume: 38 Issue: 12 Pages: 1666-1670
  • DOI: 10.1002/humu.23344
  • NAID: 120006540047
  • Peer Reviewed
• [Journal Article] C-Terminal Processing of Collagen XVII Induces Neoepitopes for Linear IgA Dermatosis Autoantibodies (2017)
  • Author(s): Toyonaga Ellen、Nishie Wataru、Izumi Kentaro、Natsuga Ken、Ujiie Hideyuki、Iwata Hiroaki、Yamagami Jun、Hirako Yoshiaki、Sawamura Daisuke、Fujimoto Wataru、Shimizu Hiroshi
  • Journal Title: Journal of Investigative Dermatology Volume: 137 Issue: 12 Pages: 2552-2559
  • DOI: 10.1016/j.jid.2017.07.831
  • NAID: 120006540048
  • Peer Reviewed / Open Access
• [Journal Article] Detection of mucous membrane pemphigoid autoantibodies by full-length BP180 enzyme-linked immunosorbent assay (2017)
  • Author(s): Izumi Kentaro、Nishie Wataru、Mai Yosuke、Ujiie Hideyuki、Iwata Hiroaki、Natsuga Ken、Shimizu Hiroshi
  • Journal Title: J Dermatol Sci Volume: 88 Issue: 2 Pages: 247-248
  • DOI: 10.1016/j.jdermsci.2017.07.005
  • Peer Reviewed
• [Journal Article] Appearance of antidesmocollin 1 autoantibodies leading to a vegetative lesion in a patient with pemphigus vulgaris (2017)
  • Author(s): Yamaguchi Y.、Shinkuma S.、Ishii N.、Takashima S.、Natsuga K.、Ujiie H.、Iwata H.、Nomura T.、Fujita Y.、Hamasaka A.、Hamasaka K.、Hashimoto T.、Shimizu H.
  • Journal Title: Br J Dermatol Volume: 178 Issue: 1 Pages: 294-295
  • DOI: 10.1111/bjd.15834
  • Peer Reviewed
• [Journal Article] Type XVII collagen coordinates proliferation in the interfollicular epidermis. (2017)
  • Author(s): Watanabe M, Natsuga K, Nishie W, Kobayashi Y, Donati G, Suzuk Si, Fujimura Y, Tsukiyama T, Ujiie H, Shinkuma S, Nakamura H, Murakami M, Ozaki M, Nagayama M, Watt F and Shimizu H
  • Journal Title: eLife Volume: 6:e26635 Pages: 1-24
  • DOI: 10.7554/elife.26635
  • NAID: 120006337772
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cutis Verticis Gyrata Fluctuation with Atopic Dermatitis Disease Activity (2017)
  • Author(s): Kosumi H、Izumi K、Natsuga K、Yamaguchi Y、Itami A、Shimizu H
  • Journal Title: Acta Derm Venereol Volume: 97 Issue: 10 Pages: 1245-1246
  • DOI: 10.2340/00015555-2750
  • Peer Reviewed / Open Access
• [Journal Article] Generalized Pustular Psoriasis (2017)
  • Author(s): Kosumi Hideyuki、Ito Takamasa、Fujita Yasuyuki、Izumi Kentaro、Maya Yuka、Yanagi Teruki、Natsuga Ken、Ujiie Hideyuki、Shinkuma Satoru、Nomura Toshifumi、Sadanobu Naoya、Shimizu Hiroshi
  • Journal Title: J Pediatr Volume: 188 Pages: 305-305.e1
  • DOI: 10.1016/j.jpeds.2017.05.058
  • Peer Reviewed
• [Journal Article] A case of recessive dystrophic epidermolysis bullosa with a novel c.6885_6898del14 mutation in the COL7A1 gene (2017)
  • Author(s): Shinkuma S, Masunaga T, Miyawaki S, Takashima S, Natsuga K, Nomura T, Fujita Y, Nakamura H, Shimizu H
  • Journal Title: J Dermatol Sci Volume: 88 Issue: 1 Pages: 139-141
  • DOI: 10.1016/j.jdermsci.2017.03.022
  • Peer Reviewed
• [Journal Article] Autoantibodies of non-inflammatory bullous pemphigoid hardly deplete type XVII collagen of keratinocytes (2017)
  • Author(s): Imafuku K, Iwata H, Kamaguchi M, Izumi K, Natsuga K, Ujiie H, Nishie W, Shimizu H
  • Journal Title: Exp Dermatol Volume: 印刷中 Issue: 12 Pages: 1171-1174
  • DOI: 10.1111/exd.13331
  • NAID: 120006540054
  • Peer Reviewed
• [Journal Article] Psoriasiform mycosis fungoides masquerading as tumourous plaques (2017)
  • Author(s): Yamaguchi Y, Fujita Y, Hirata Y, Nishimura M, Shinkuma S, Natsuga K, Hida T, Kato N, Shimizu H
  • Journal Title: Eur J Dermatol Volume: 印刷中 Issue: 3 Pages: 295-296
  • DOI: 10.1684/ejd.2017.2971
  • Peer Reviewed
• [Presentation] 表皮の恒常性維持と外的刺激に対する応答 (2019)
  • Author(s): 夏賀 健
  • Organizer: 第1回炎症性皮膚疾患集中セミナー
  • Invited
• [Presentation] Clavus serves as a model of epidermal stem cell responses to mechanical forces (2018)
  • Author(s): Natsuga K, Watanabe M, Hata H, Kobayashi Y, Nagayama M, Shimizu H
  • Organizer: International Investigative Dermatology 2018
  • Int'l Joint Research
• [Presentation] Organization of the epidermal basement membrane zone determined through super-resolution microscopy (2018)
  • Author(s): Natsuga K, Watanabe M, Shimizu H
  • Organizer: 7th SSSR and SCUR meeting
  • Int'l Joint Research
• [Presentation] 表皮化水疱症 発症機序/新規治療法の最新の進歩 (2018)
  • Author(s): 夏賀 健
  • Organizer: 第117回日本皮膚科学会総会
  • Invited
• [Presentation] Abnormalities in laminin-332 have post-translational effects on laminin γ2 (2017)
  • Author(s): Natsuga K, Nishie W, Watanabe M, Nakamura H, Shinkuma S, Shimizu H
  • Organizer: EB2017 - 5th World Conference of EB Research & 4th Conference of EB-CLINET
  • Int'l Joint Research