Establishment of cicatricial alopecia animal models

• Project/Area Number: 16K10120
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Dermatology
• Research Institution: Hokkaido University
• Principal Investigator: Nakamura Hideki 北海道大学, 医学研究院, 助手 (60435956)
• Co-Investigator(Kenkyū-buntansha): 清水 宏 北海道大学, 医学研究院, 教授 (00146672) ; 西江 渉 北海道大学, 医学研究院, 准教授 (20443955) ; 夏賀 健 北海道大学, 大学病院, 講師 (70645457)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 皮膚病態学 / 瘢痕型脱毛症 / 17型コラーゲン

Outline of Final Research Achievements

Cicatricial alopecia is a type of hair loss characterized by loss of hair follicles and surrounding fibrosis. The aim of this study was to elucidate the mechanism of cicatricial alopecia by analyzing the hair follicles in the blistered skin of mice in detail. A major finding was a delay in hair follicle development/cycling at the re-epithelialized wounds after blistering. At the same time, infiltration of inflammatory cells was poor at the site where several layers of epithelization were completed, and there was no difference compared to the intact site. Taken together, these results indicate that the early stage of cicatricial alopecia involves less inflammation, with the proliferation of epithelial cells required for hair follicle growth directed toward re-epithelialization.

Academic Significance and Societal Importance of the Research Achievements

瘢痕型脱毛症は、全身性エリテマトーデスなどの膠原病や毛孔性扁平苔癬などでしばしば見られる症状であり、初期段階において毛包をアタックする炎症細胞浸潤を抑制するための、十分な抗炎症療法が重要であると考えられてきた。しかしながら、本研究の成果で、むしろ脱毛の初期段階では毛包上皮細胞の増殖が創傷の治癒へと傾いてしまい、十分に毛包の成長へと向けられていないことが観察されたため、抗炎症療法のみならず、上皮細胞の増殖・分化の調整が早期治療に重要である可能性が示唆された。

Research Products

• [Journal Article] Efficient gene reframing therapy for recessive dystrophic epidermolysis bullosa using CRISPR/Cas9 (2019)
  • Author(s): Takashima Shota、Shinkuma Satoru、Fujita Yasuyuki、Nomura Toshifumi、Ujiie Hideyuki、Natsuga Ken、Iwata Hiroaki、Nakamura Hideki、Vorobyev Artem、Abe Riichiro、Shimizu Hiroshi
  • Journal Title: Journal of Investigative Dermatology Volume: in press Issue: 8 Pages: 1711-1721
  • DOI: 10.1016/j.jid.2019.02.015
  • Peer Reviewed / Int'l Joint Research
• [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] 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] The first familial cases of epidermolysis bullosa simplex, generalized severe with p.Asn176Ser in KRT5 revealing the clinical chronology (2017)
  • Author(s): Sugai T, Shinkuma S, Inafuku K, Takashima S, Nomura T, Fujita Y, Nakamura H, Shimizu H
  • Journal Title: Journal of the European Academy of Dermatology and Venereology Volume: in press Issue: 5
  • DOI: 10.1111/jdv.14036
  • Peer Reviewed / Acknowledgement Compliant
• [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] 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] Extracellular cleavage of collagen XVII is essential for correct cutaneous basement membrane formation. (2016)
  • Author(s): Nishimura M, Nishie W, Shirafuji Y, Shinkuma S, Natsuga K, Nakamura H, Sawamura D, Iwatsuki K, Shimizu H
  • Journal Title: Hum Mol Genet Volume: 15;25(2) Issue: 2 Pages: 328-39
  • DOI: 10.1093/hmg/ddv478
  • NAID: 120005868259
  • Peer Reviewed / Open Access
• [Journal Article] Epitope-dependent pathogenicity of Abs targeting a major bullous pemphigoid autoAg collagen XVII/BP180 (2016)
  • Author(s): Wada M, Nishie W*, Ujiie H, Izumi K, Iwata H, Natsuga K, Nakamura H, Kitagawa Y, Shimizu H:
  • Journal Title: J Invest Dermatol Volume: 136 Pages: 938-946
  • Peer Reviewed
• [Presentation] Cultured epidermal autograft from clinically revertant skin in recessive dystrophic epidermolysis bullosa. (2018)
  • Author(s): Fujita Y, Matsumura W, Shinkuma S, Takashima S, Suzuki S, Nomura T, Nakamura H, Inoie M, Shimizu H.
  • Organizer: Internatinal Investigative Derematology 2018. Orlando, Florida.
  • Int'l Joint Research
• [Presentation] Differences in collagen XVII expression between skin and oral mucosa affect the pathogenicity of pemphigoid IgG (2018)
  • Author(s): .Kamaguchi M, Iwata H, Ujiie H, Natsuga K, Nishie W, Asaka T, Shimizu H, Kitagawa Y.
  • Organizer: 14th Biennial Congress of the European Association of Oral Medicine Gotenbrug, Sweden.
  • Int'l Joint Research
• [Presentation] A case of recessive dystrophic epidermolysis bullosa with a novel c.6885_6898del14 mutation. (2017)
  • Author(s): Shinkuma S, Masunaga T, Miyawaki S, Takashima S, Natsuga K, Nomura T, Fujita Y, Nakamura H, Shimizu H
  • Organizer: The 76th Annual Meeting of the Society for Investigative Dermatology.
  • Int'l Joint Research
• [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
  • Int'l Joint Research
• [Presentation] Two families of nail-patella syndrome with splice site mutations (2017)
  • Author(s): Shinkuma S, Nakamura H, Takashima S, Nomura T, Fujita Y, Hasegawa S, Sato-Matsumura K, Shimizu H, Abe R
  • Organizer: The 47th Annual European Society for Dermatological Research Meeting
  • Int'l Joint Research
• [Presentation] Long lasting epithelization after cultured epidermal autograft with revertant mosaicism in recessive dystrophic epidermolysis bullosa (2017)
  • Author(s): Matsumura W, Fujita Y, Takashima S, Nakayama C, Ujiie I, Shinkuma S, Nakamura H, Sawamura D, Inoie M, Shimizu H
  • Organizer: DEBRA International Congress 2017
  • Int'l Joint Research
• [Presentation] Normal appearance of epidermal basement membrane zone in nail-patella syndrome patients (2017)
  • Author(s): Shinkuma S, Nakamura H, Takashima S, Nomura T, Fujita Y, Matsumura K, Shimizu H, Abe R
  • Organizer: The 42nd Annual Meeting of the Japanese Society for Investigative Dermatology
• [Presentation] Defective binding of plectin and collagen XVII leads to epidermolysis bullosa simplex. (2016)
  • Author(s): Natsuga K, Nihsie W, Nishimura M, Shinkuma S, Watanabe M, Izumi K, Nakamura H, Hirako Y, Shimizu H
  • Organizer: The 46th Annual European Society for Dermatological Research meeting.
  • Place of Presentation: Technical University of Munich, Munich, Germany
  • Year and Date: 2016-09-07
  • Int'l Joint Research
• [Presentation] 皮膚基底膜構築における17型コラーゲン細胞外領域切断の生理機能の解析 (2016)
  • Author(s): 西村真智子, 西江渉, 新熊悟, 夏賀健, 中村秀樹, 白藤宜紀, 岩月啓氏, 澤村大輔, 清水宏
  • Organizer: 第407回日本皮膚科学会北海道地方会
  • Place of Presentation: 札幌医大、札幌市