KEIO RESEARCHERS INFORMATION SYSTEM

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Research Areas 【 Display / hide 】

• Life Science / Cell biology

• Life Science / Plastic and reconstructive surgery

Papers 【 Display / hide 】

Papers 【 Display / hide 】

• Actin mesh in Re-epithelialization during skin regeneration in adult newt (Cynops pyrrhogaster)

  Yu Liou, Nobuko Moritoki, Tomoko Shindo, Tatsuyuki Ishii, Kazuo Kishi

  Regenerative Therapy (Elsevier BV)  29   254 - 261 2025.06

  ISSN  2352-3204

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  Introduction: Studies have highlighted the role of actin cables in embryonic scarless wound healing across various species. However, evidence for similar structures in adult animals remains lacking. Adult newts, known for their exceptional skin regeneration capabilities, are considered promising models for postnatal human studies. This study investigated actin fiber formation and alignment during re-epithelialization in the Japanese fire-bellied newt (Cynops pyrrhogaster). Methods: Full-thickness skin excisions were performed, and actin structures were analyzed using immunohistochemistry and electron microscopy. The role of actin in re-epithelialization was assessed by inhibiting its formation with cytochalasin B. Myosin, an interacting cytoskeletal molecule, was examined through immunohistochemistry, while E-cadherin, an adhesion molecule, was analyzed using both immunohistochemistry and electron microscopy. Results: Rather than an actin cable a mesh-like actin structure, termed the “actin mesh,” was identified via immunohistochemical analysis. The actin mesh developed alongside wound epidermis extension and disappeared following complete re-epithelialization. Inhibition of actin formation delayed re-epithelialization, although the overall healing process showed no significant difference from the control group. Immunohistochemistry revealed the presence of myosin II and E-cadherin alongside Filamentous actin. Electron microscopy further demonstrated actin-rich structures in the wound epidermis compared to normal skin and confirmed E-cadherin-mediated cell-cell adhesion in the wound area. Conclusions: The actin mesh plays a critical role in facilitating rapid re-epithelialization in adult newts, presenting a valuable model for studying scarless wound healing in adult organisms. The involvement of interacting molecules such as myosin and E-cadherin provides insights into the underlying mechanisms of this process. This model offers potential applications for addressing intractable wounds in humans.

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• Navitoclax (ABT-263) Rejuvenates Human Skin by Eliminating Senescent Dermal Fibroblasts in a Mouse/Human Chimeric Model

  Takaya K., Ishii T., Asou T., Kishi K.

  Rejuvenation Research 26 ( 1 ) 9 - 20 2023.02

  ISSN  15491684

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  Chronic senescence, such as aging, contributes to age-related tissue dysfunction and disease development. The accumulation of senescent fibroblasts and the senescence-associated secretory phenotype is particularly implicated in this process. Removal of senescent cells has been reported to prevent tissue dysfunction and to extend the life span during aging. ABT-263 (navitoclax), which inhibits antiapoptotic proteins, is a leading antiaging drug; however, its role in human skin aging is unclear. This study aimed to determine the rejuvenating effects of ABT-263 on aging skin using a human skin graft mouse model. We assessed the viability of ABT-263-treated skin fibroblasts after inducing senescence. Aged human skin was transplanted under the back skin of nude mice and injected intraperitoneally with the drug or control. Analysis of the skin specimens revealed that ABT-263 induced selective elimination of senescent dermal fibroblasts. Senescent human skin treated with ABT-263 exhibited a decrease in the number of senescent cells and in the expression of aging-related secretory phenotype molecules, such as matrix metalloproteinases and interleukins and an increase in collagen density. Our results indicate that selective removal of senescent skin cells with ABT-263 can improve the aging phenotype of human skin without side effects. ABT-263 is, thus, a novel potential therapeutic agent for skin aging.

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• Wrinkle Feature Analysis using Dermo-camera Images

  浅野祐太, 西澤巧, 梶田大樹, 石井龍之, 貴志和生, 佐藤いまり

  日本医用画像工学会大会予稿集(CD-ROM) ((一社)日本医用画像工学会)  41回   162 - 163 2022.07

  ISSN  0288-450X

  　View Summary

  人間の皮膚は,外的要因から体内を守り,恒常性を保つ重要な役割を担う器官であるが,一方で美容的な観点からも皮膚の状態評価が重要である.皮膚の評価項目の一つとして,皮膚のシワ・キメと呼ばれる肌の細かい凸凹の形状パターンから皮膚の状態を評価するが,皮膚画像からシワ・キメは判別しづらく,シワ・キメを正確に可視化することは困難である.そこで,ダーモカメラで撮影された通常の画像(「非偏光画像」),および偏光板を用いて直接反射光成分を除いた画像(「偏光画像」)の二枚の画像を用いたシワ・キメを可視化する画像処理手法を開発した.非偏光画像および偏光画像の差分特徴量を抽出し,皮膚の色による背景輝度のムラを削減することで正確なシワ・キメの可視化を行う.さらに,シワ・キメの可視化画像についてのGabor特徴量を解析することで,シワ・キメの間隔や方向性などのパターンを定性的および定量的に評価した.(著者抄録)

• Glutaminase inhibitors rejuvenate human skin via clearance of senescent cells: a study using a mouse/human chimeric model

  Takaya K., Ishii T., Asou T., Kishi K.

  Aging 14 ( 22 ) 8914 - 8926 2022

  ISSN  19454589

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  Skin aging caused by various endogenous and exogenous factors results in structural and functional changes to skin components. However, the role of senescent cells in skin aging has not been clarified. To elucidate the function of senescent cells in skin aging, we evaluated the effects of the glutaminase inhibitor BPTES (bis-2-(5-phenylacetamido-1, 3, 4-thiadiazol-2-yl)ethyl sulfide) on human senescent dermal fibroblasts and aged human skin. Here, primary human dermal fibroblasts (HDFs) were induced to senescence by long-term passaging, ionizing radiation, and treatment with doxorubicin, an anticancer drug. Cell viability of HDFs was assessed after BPTES treatment. A mouse/human chimeric model was created by subcutaneously transplanting whole skin grafts from aged humans into nude mice. The model was treated intraperitoneally with BPTES or vehicle for 30 days. Skin samples were collected and subjected to reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blotting, and histological analysis. BPTES selectively eliminated senescent dermal fibroblasts regardless of the method used to induce senescence; aged human skin grafts treated with BPTES exhibited increased collagen density, increased cell proliferation in the dermis, and decreased aging-related secretory phenotypes, such as matrix metalloprotease and interleukin. These effects were maintained in the grafts 1 month after termination of the treatment. In conclusion, selective removal of senescent dermal fibroblasts can improve the skin aging phenotype, indicating that BPTES may be an effective novel therapeutic agent for skin aging.

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• Skin Wound Healing of the Adult Newt, Cynops pyrrhogaster: A Unique Re-Epithelialization and Scarless Model

  Tatsuyuki Ishii, Ikkei Takashimizu, Martin Miguel Casco-Robles, Yuji Taya, Shunsuke Yuzuriha, Fubito Toyama, Fumiaki Maruo, Kazuo Kishi, Chikafumi Chiba

  Biomedicines (MDPI AG)  9 ( 12 ) 1892 - 1892 2021.12

  ISSN  2227-9059

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  In surgical and cosmetic studies, scarless regeneration is an ideal method to heal skin wounds. To study the technologies that enable scarless skin wound healing in medicine, animal models are useful. However, four-limbed vertebrates, including humans, generally lose their competency of scarless regeneration as they transit to their terrestrial life-stages through metamorphosis, hatching or birth. Therefore, animals that serve as a model for postnatal humans must be an exception to this rule, such as the newt. Here, we evaluated the adult newt in detail for the first time. Using a Japanese fire-bellied newt, Cynops pyrrhogaster, we excised the full-thickness skin at various locations on the body, and surveyed their re-epithelialization, granulation or dermal fibrosis, and recovery of texture and appendages as well as color (hue, tone and pattern) for more than two years. We found that the skin of adult newts eventually regenerated exceptionally well through unique processes of re-epithelialization and the absence of fibrotic scar formation, except for the dorsal-lateral to ventral skin whose unique color patterns never recovered. Color pattern is species-specific. Consequently, the adult C. pyrrhogaster provides an ideal model system for studies aimed at perfect skin wound healing and regeneration in postnatal humans.

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Reviews, Commentaries, etc. 【 Display / hide 】

Reviews, Commentaries, etc. 【 Display / hide 】

• ゲノムや遺伝子配列が明らかにされていない動物種でも遺伝子発現の解析は可能か?

  田谷 雄二, 坪崎 健斗, 埴 太宥, 工藤 朝雄, 佐藤 かおり, 添野 雄一, 藤田 和也, 貴志 和生, 石井 龍之, 千葉 親文

  Journal of Oral Biosciences Supplement ((一社)歯科基礎医学会)  2024   [P3 - 1 2024.11

  ISSN  2187-2333

• 【それぞれの創傷治癒】イモリの創傷治癒

  石井 龍之, 高清水 一慶, 貴志 和生

  形成外科 (克誠堂出版(株))  67 ( 増刊 ) S2 - S6 2024.06

  ISSN  0021-5228

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  ＜文献概要＞はじめに　究極の医療とは何か。SF映画や漫画「ドラゴンボール」のピッコロ大魔王のごとく,四肢をまるごと自己再生させるような医療が実現できれば,それはまさに究極と呼ぶにふさわしいのではないだろうか。自己再生が可能となれば,事故で手足を失ったり,病変切除による臓器欠損が生じたりしても,再生誘導で元どおりにすれば万時解決できる夢のような治療である。現在の医療では到底不可能な技術だが,世の中にはすでに自己再生を可能とする生物たちがいる。両生類はその代表格であるが,とりわけ日本固有種であるアカハライモリは生涯にわたり強い再生力を維持する点で他と一線を画しており,近年注目を集めている。本稿では,イモリの創傷治癒について紹介するとともに,今後の再生医療研究の展望について述べたい。

• それぞれの創傷治癒 1.イモリの創傷治癒

  石井龍之, 高清水一慶, 貴志和生

  形成外科 67 2024

  ISSN  0021-5228

• 口唇部静脈奇形に対するドライアイスを用いた凍結療法の治療経験

  荒牧典子, 石井龍之, 貴志和生

  日本形成外科学会総会・学術集会プログラム・抄録集 67th 2024

• ドライアイスを利用した先天性色素性母斑の剛毛治療

  石井龍之, 加藤達也, 荒牧典子, 貴志和生

  日本形成外科学会総会・学術集会プログラム・抄録集 67th 2024

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Research Projects of Competitive Funds, etc. 【 Display / hide 】

Research Projects of Competitive Funds, etc. 【 Display / hide 】

• 傷跡を残さない治療を可能とする細胞温度感受性を利用した低侵襲細胞 選択的凍結医療機器の開発

  2025.06

  -

  Present

  日本医療研究開発機構（AMED）, 橋渡し研究プログラムPreF, Principal investigator

• イモリ血中エクソソームを利用した革新的再生医療の創出

  2025.04

  -

  2027.03

  日本学術振興会, Grants-in-Aid for Scientific Research, Grant-in-Aid for Early-Career Scientists, Principal investigator

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  本研究は、特異な再生力をもつイモリの血液から単離・精製したエクソソームが、我々哺乳 類に創傷再生効果をもたらすかを検証するものであり、イモリ型の臓器再生医療の実現に向 けた挑戦である。申請者らは数ある再生生物の中でもイモリが独自の再生能を有しており、 イモリ血液中に再生関連因子が含まれる可能性があるところまで突き止めた。また、種を越 えてマウス細胞にも線維化抑制能をもたらす可能性が示されており、イモリ血液由来のエク ソソームを単離・精製し、内包されるmiRNAの解析を中心にマウスやヒト細胞との相同性を 解明することで、革新的な再生医療の創出に繋げるものである。

• 胎仔皮膚再生におけるfibroblastとmacrophageの相互作用に働くエクソソームの探究

  2024.04

  -

  2027.03

  日本学術振興会, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), No Setting

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  「瘢痕を残さない治癒(scarless wound healing)」は現時点では実現不可能である。しかし、 胎生13日以前のマウスでは皮膚の完全な再生が可能である。当研究室ではこれまで主に線維芽細胞とマクロファージに注目して研究を行ってきた。近年エクソソームと呼ばれる細胞外小胞が注目を集めており、本研究では今まで解明されなかった完全に皮膚が再生する胎生13 日のマウスの線維芽細胞とマクロファージから、エクソソームを抽出し、内包されるmiRNA の絞り込みを行うとともに、エクソソーム自体や内包される分子の投与により、「scarless wound healing」の実現を目的とする。

• 熱傷”イモリ”モデルを用いた無瘢痕皮膚再生における傷上皮の作用機序の解明

  2024.04

  -

  2027.03

  日本学術振興会, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), No Setting

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  ヒトは修復による瘢痕形成が生じるために深い傷を再生させることができない。瘢痕に関する研究は、適切なモデル動物がないためにその発生機序については不明な点も多い。近年、四肢や様々な臓器の一部を失っても驚異的な再生力を持つアカハライモリを用いて、皮膚も瘢痕形成なく再生できることを示してきた。本研究は、ヒトと異なる創傷治癒機構である”傷上皮”が炎症を早期に鎮静化させることから、”傷上皮”を阻害するモデルと傷の中でもより炎症が遷延し、治療に難渋する熱傷モデルをイモリで作製し、その治癒過程を解析することで、無瘢痕皮膚再生のメカニズムと”傷上皮”の機能を明らかにするものである。

• ミトコンドリア温度感受性を利用した革新的細胞選択的凍結治療の開発

  2024.04

  -

  2025.03

  JKiC, 学術開発プロジェクト, Principal investigator

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Courses Taught 【 Display / hide 】

Courses Taught 【 Display / hide 】

• LECTURE SERIES, PLASTIC AND RECONSTRUCTIVE SURGERY

  2025