創傷治癒における上皮系幹細胞のダイナミクス

2017 Fiscal Year Research-status Report

• Project/Area Number: 17K16317
• Research Institution: Hokkaido University
• Principal Investigator: 夏賀 健 北海道大学, 大学病院, 講師 (70645457)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: 幹細胞 / 創傷治癒

Outline of Annual Research Achievements

一般的な実験動物に対する創傷治癒実験よりも規模が微小な創傷の治癒過程を観察することで、より詳細な創傷の再上皮化までのプロセスを解析している。初年度は主に組織学的な解析を行った。野生型マウス（C57BL/6)背部皮膚に対する微小創傷では、アルカリフォスファターゼ陽性の毛乳頭は創傷作成部位の真皮側に残存する。創傷治癒過程を経時的に詳細に観察したところ、再上皮化する表皮細胞ではアルファ6インテグリン、パンサイトケラチンが創傷作成の24時間後には発現するようになり、72時間後には重層化した表皮が完成する。この場合、表皮顆粒層のマーカーであるロリクリンも微小創傷の72時間後には発現が認められるため、表皮の分化も完成したと結論づけられる。微小創傷の作成とlineage tracingの手法を組み合わせることで、微小創傷部位の上皮化時の、各種幹細胞の寄与を明らかにしている。特に、K14-CreERTマウス（Jackson laboratoryから入手)とR26R-H2B-mCherryマウス（RIKEN CLSTから入手)の交配によって作出されるK14-CreERT;R26R-H2B-mCherryマウスへタモキシフェンを投与して、Creリコンビナーゼの誘導から毛包間表皮幹細胞（ケラチン14陽性、核へのmCherryの発現を共焦点顕微鏡で観察）の細胞系譜を確認した。微小創傷部位では、創傷辺縁に毛包間表皮幹細胞からの子孫の細胞群が集塊をなしていた。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

平成29年度に予定していた、微小創傷部位の形態学的・組織学的観察は完了している。また、平成29年度から30年度の2年間にわたって予定していたlineage tracingについても、既に開始しており、一定の成果を上げていることから、おおむね順調に進展していると評価した。

Strategy for Future Research Activity

Lineage tracing実験の観察する個体数を増加させ、結果として得られる蛍光色素陽性細胞を定量評価する。

Research Products

• [Int'l Joint Research] キングズカレッジロンドン(英国)
  • Country Name: UNITED KINGDOM
  • Counterpart Institution: キングズカレッジロンドン
• [Int'l Joint Research] トリノ大学(イタリア)
  • Country Name: ITALY
  • Counterpart Institution: トリノ大学
• [Int'l Joint Research]
  • # of Other Countries: 2
• [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: 45 Pages: e260～e261
  • DOI: 10.1111/1346-8138.14287
  • 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 Pages: 1260～1267
  • DOI: 10.1016/j.jid.2018.01.005
  • 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 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: British Journal of Dermatology Volume: 178 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 Pages: 印刷中
  • DOI: 10.1111/exd.13550
  • 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: 印刷中 Pages: 印刷中
  • DOI: 10.1016/j.jid.2018.03.002
  • 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 Pages: 印刷中
  • 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 Pages: 印刷中
  • 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 Pages: 印刷中
  • DOI: 10.1111/1346-8138.14180
  • 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 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 Ken、Nishie Wataru、Nishimura Machiko、Shinkuma Satoru、Watanabe Mika、Izumi Kentaro、Nakamura Hideki、Hirako Yoshiaki、Shimizu Hiroshi
  • Journal Title: Hum Mutat Volume: 38 Pages: 1666～1670
  • DOI: 10.1002/humu.23344
  • 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: J Invest Dermatol Volume: 137 Pages: 2552～2559
  • DOI: 10.1016/j.jid.2017.07.831
  • Peer Reviewed
• [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 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 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, Suzuki S, Fujimura Y, Tsukiyama T, Ujiie H, Shinkuma S, Nakamura H, Murakami M, Ozaki M, Nagayama M, Watt FM, Shimizu H
  • Journal Title: Elife Volume: 6 Pages: e26635
  • DOI: 10.7554/eLife.26635
  • 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 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 Satoru、Masunaga Tae、Miyawaki Saori、Takashima Shota、Natsuga Ken、Nomura Toshifumi、Fujita Yasuyuki、Nakamura Hideki、Shimizu Hiroshi
  • Journal Title: J Dermatol Sci Volume: 88 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 Keisuke、Iwata Hiroaki、Kamaguchi Mayumi、Izumi Kentaro、Natsuga Ken、Ujiie Hideyuki、Nishie Wataru、Shimizu Hiroshi
  • Journal Title: Exp Dermatol Volume: 26 Pages: 1171～1174
  • DOI: 10.1111/exd.13331
  • 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, Nomura T, Hida T, Kato N, Shimizu H
  • Journal Title: Eur J Dermatol Volume: 27 Pages: 295-296
  • DOI: 10.1684/ejd.2017.2971
  • Peer Reviewed
• [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