2024年06月, 日本皮膚科学会, 第438回日本皮膚科学会北海道地方会ベストスライド賞　　　　　　　　　　　　　　　

2023年12月, 北海道大学医学部同窓会, 05年度フラテ研究奨励賞　　　　　　　　　　　　　　　
高島翔太

2020年12月, マルホ, 第21回マルホ研究賞　　　　　　　　　　　　　　　

2019年06月, 日本皮膚科学会, 第418回日本皮膚科学会北海道地方会ベストスライド賞　　　　　　　　　　　　　　　

2018年03月, 国際研究皮膚科学会, Intersociety Young Fellow Collegiality Awards　　　　　　　　　　　　　　　

Multiple Acantholytic Acanthomas in Junctional Epidermolysis Bullosa.
Sota Itamoto, Ken Natsuga, Takashi Seo, Shota Takashima, Hideyuki Ujiie
Acta dermato-venereologica, 104, adv42258, 2024年11月19日, ［国際誌］
英語, 研究論文（学術雑誌）

Spatial confinement induces reciprocating migration of epidermal keratinocytes and forms triphasic epithelia
Takuma Nohara, Junichi Kumamoto, Yosuke Mai, Mayuna Shimano, Sora Kato, Hiroyuki Kitahata, Hideki Nakamura, Shota Takashima, Mika Watanabe, Masaharu Nagayama, Tsukasa Oikawa, Hideyuki Ujiie, Ken Natsuga
Cold Spring Harbor Laboratory, 2024年11月13日
Epithelial cells undergo epithelial–mesenchymal transition (EMT) during migration and regain their epithelial phenotype in the post-migration phase (mesenchymal–epithelial transition; MET). We established an experimental system that reproduced three-dimensional triphasic epithelia, i.e., the original epithelium, its EMT, and MET. Keratinocytes (KCs), skin epithelial cells, placed on a microporous membrane migrated through 3.0-um or larger micropores. The 3.0-um-pored membrane induced an epithelial structure with three states: stratified KCs above the membrane, KCs showing EMT within the micropores, and a new stratified epithelium under the membrane. The membrane with larger micropores failed to maintain the triphasic epithelia. Live imaging revealed that KCs moved in a reciprocating manner, with actin-rich filopodia-like KC structures extending into and out of the 3.0-um micropores, while the cells migrated unidirectionally into larger micropores. Piezo1 and keratin 6 were identified as negative modulators of KC entry to and exit from the 3.0-um micropores. These results demonstrate that non-cancerous epithelial cells migrate through confined spaces in a reciprocating manner, which might help form triphasic epithelia, recapitulating wound healing processes.

Atypical manifestations of hemangiomas in epidermolysis bullosa.
S Itamoto, K Natsuga, S Takashima, H Ujiie
The Journal of dermatology, 2024年06月14日, ［査読有り］, ［国際誌］
英語

Pseudolymphoma on the face involving the conjunctiva.
Akihiro Orita, Shota Takashima, Norihiro Yoshimoto, Atsushi Narahira, Yosuke Mai, Ken Arita, Satoru Kase, Wataru Nishie, Hideyuki Ujiie
Clinical and experimental dermatology, 49, 5, 521, 523, 2024年04月23日, ［国際誌］
英語, 研究論文（学術雑誌）

Alternative mRNA splicing events and regulators in epidermal differentiation.
Shota Takashima, Wujianan Sun, Auke B C Otten, Pengfei Cai, Shaohong Isaac Peng, Elton Tong, Jolina Bui, McKenzie Mai, Oyumergen Amarbayar, Binbin Cheng, Rowen Jane Odango, Zongkai Li, Kun Qu, Bryan K Sun
Cell reports, 43, 3, 113814, 113814, 2024年03月26日, ［国際誌］
英語, 研究論文（学術雑誌）, Alternative splicing (AS) of messenger RNAs occurs in ∼95% of multi-exon human genes and generates diverse RNA and protein isoforms. We investigated AS events associated with human epidermal differentiation, a process crucial for skin function. We identified 6,413 AS events, primarily involving cassette exons. We also predicted 34 RNA-binding proteins (RBPs) regulating epidermal AS, including 19 previously undescribed candidate regulators. From these results, we identified FUS as an RBP that regulates the balance between keratinocyte proliferation and differentiation. Additionally, we characterized the function of a cassette exon AS event in MAP3K7, which encodes a kinase involved in cell signaling. We found that a switch from the short to long isoform of MAP3K7, triggered during differentiation, enforces the demarcation between proliferating basal progenitors and overlying differentiated strata. Our findings indicate that AS occurs extensively in the human epidermis and has critical roles in skin homeostasis.

Successful treatment of multicentric Castleman's disease associated with dystrophic epidermolysis bullosa using anti-interleukin-6 receptor antibody.
Satsuki Naruse, Shota Takashima, Yasuyuki Fujita, Hiroshi Kataoka, Nobuaki Kawamura, Ken Natsuga, Hideyuki Ujiie
The Journal of dermatology, 2024年03月14日, ［国際誌］
英語

Development of a nutritionally balanced, melt-in-the-mouth chocolate for patients with epidermolysis bullosa.
Kosei Nakamura, Shota Takashima, Takuma Nohara, Mika Watanabe, Ken Natsuga, Hideyuki Ujiie
The Journal of dermatology, 50, 12, 1640, 1643, Wiley, 2023年12月, ［国際誌］
英語, 研究論文（学術雑誌）, Abstract

Epidermolysis bullosa (EB) is a group of inherited blistering disorders that primarily affect the skin and mucous membranes of the digestive tract, which can lead to poor nutritional status. Dietary supplements and nutritional support methods, such as nasogastric tubes and gastrostomy, have been employed to improve the nutritional status of patients with EB; however, few foods are suitable for enjoyable eating with family and friends. Here, we introduce a nutritionally balanced, melt‐in‐the‐mouth chocolate called andew, which was specifically designed for patients with EB. The andew chocolate is nutritionally superior and melts more easily than traditional chocolates, thus it is suitable for patients with EB, who are prone to oral erosions. Patients responded more favorably to the taste and texture of andew than to those of other dietary supplements. Not only does andew provide nutritional benefits, but it also promotes enjoyable eating with family members and friends, which could positively impact patients' mental health.

Dermal discoloration due to osmium tetroxide.
Satsuki Naruse, Shota Takashima, Ken Natsuga, Hideyuki Ujiie
Clinical toxicology (Philadelphia, Pa.), 61, 11, 1004, 1005, 2023年11月, ［国際誌］
英語, 研究論文（学術雑誌）, INTRODUCTION: Osmium tetroxide is a strong oxidizing agent. After dermal exposure to osmium tetroxide, skin discoloration and red papules can occur. We describe a patient with skin discoloration due to osmium tetroxide. CASE SUMMARY: A 25-year-old postgraduate student unintentionally exposed his hand to osmium tetroxide while working in a laboratory setting. After immediate washing, he sought medical care due to left middle finger discoloration. He reported no discomfort in the affected area. Thorough water rinsing was continued, and corticosteroid ointment was applied. IMAGES: Our patient developed dark brown pigmentation on the ventral side of the left middle finger. The pigmentation disappeared one week later. CONCLUSION: Osmium tetroxide may induce dark brown skin discoloration.

四酸化オスミウムによる化学熱傷により色素沈着を生じた1例　　　　　　　　　　　　　　　
成瀬 早紀, 高島 翔太, 夏賀 健, 氏家 英之
日本皮膚科学会雑誌, 133, 9, 2182, 2182, (公社)日本皮膚科学会, 2023年08月
日本語

抗真菌薬外用により急速に上皮化した難治性うっ滞性皮膚潰瘍の1例　　　　　　　　　　　　　　　
澁佐 知歩, 宮澤 元, 渡邉 美佳, 黒澤 卓, 長田 悠里, 眞井 翔子, 得地 景子, 今福 恵輔, 高島 翔太, 氏家 英之, 細川 一義
日本皮膚科学会雑誌, 133, 9, 2183, 2183, (公社)日本皮膚科学会, 2023年08月
日本語

A pilot study using immunohistochemical staining to characterize dihydropyrimidine dehydrogenase expression in keratinocyte neoplasms.
Ogechi Ikediobi, Jennifer Y Sui, Caitlyn Kellogg, Andrea Roso Mares, Shota Takashima, Julia D Bertini, Brianne Daniels, Brian Hinds, Bryan K Sun
JAAD international, 11, 90, 91, 2023年06月, ［国際誌］
英語, 研究論文（学術雑誌）

表皮水疱症に合併したacantholytic acanthomaの組織学的検討　　　　　　　　　　　　　　　
板本 想太, 夏賀 健, 高島 翔太, 氏家 英之
日本皮膚科学会雑誌, 133, 3, 540, 540, (公社)日本皮膚科学会, 2023年03月
日本語

表皮水疱症に合併した血管腫の2例　　　　　　　　　　　　　　　
板本 想太, 夏賀 健, 高島 翔太, 氏家 英之
日本皮膚科学会雑誌, 133, 2, 272, 272, (公社)日本皮膚科学会, 2023年02月
日本語

Cas9-guided haplotyping of three truncation variants in autosomal recessive disease.
Ken Natsuga, Yoshikazu Furuta, Shota Takashima, Takuma Nohara, Hsin-Yu Huang, Satoru Shinkuma, Hideki Nakamura, Yousuke Katsuda, Hideaki Higashi, Chao-Kai Hsu, Satoshi Fukushima, Hideyuki Ujiie
Human mutation, 43, 7, 877, 881, 2022年07月, ［国際誌］
英語, 研究論文（学術雑誌）, An autosomal recessive disease is caused by biallelic loss-of-function mutations. However, when more than two disease-causing variants are found in a patient's gene, it is challenging to determine which two of the variants are responsible for the disease phenotype. Here, to decipher the pathogenic variants by precise haplotyping, we applied nanopore Cas9-targeted sequencing (nCATS) to three truncation COL7A1 variants detected in a patient with recessive dystrophic epidermolysis bullosa (EB). The distance between the most 5' and 3' variants was approximately 19 kb at the level of genomic DNA. nCATS successfully demonstrated that the most 5' and 3' variants were located in one allele while the variant in between was located in the other allele. Interestingly, the proband's mother, who was phenotypically intact, was heterozygous for the allele that harbored the two truncation variants, which could otherwise be misinterpreted as those of typical recessive dystrophic EB. Our study highlights the usefulness of nCATS as a tool to determine haplotypes of complicated genetic cases. Haplotyping of multiple variants in a gene can determine which variant should be therapeutically targeted when nucleotide-specific gene therapy is applied.

Collagen XVII deficiency alters epidermal patterning.
Yunan Wang, Hiroyuki Kitahata, Hideyuki Kosumi, Mika Watanabe, Yu Fujimura, Shota Takashima, Shin-Ichi Osada, Tomonori Hirose, Wataru Nishie, Masaharu Nagayama, Hiroshi Shimizu, Ken Natsuga
Laboratory investigation; a journal of technical methods and pathology, 102, 6, 581, 588, 2022年06月, ［国際誌］
英語, 研究論文（学術雑誌）, Vertebrates exhibit patterned epidermis, exemplified by scales/interscales in mice tails and grooves/ridges on the human skin surface (microtopography). Although the role of spatiotemporal regulation of stem cells (SCs) has been implicated in this process, the mechanism underlying the development of such epidermal patterns is poorly understood. Here, we show that collagen XVII (COL17), a niche for epidermal SCs, helps stabilize epidermal patterns. Gene knockout and rescue experiments revealed that COL17 maintains the width of the murine tail scale epidermis independently of epidermal cell polarity. Skin regeneration after wounding was associated with slender scale epidermis, which was alleviated by overexpression of human COL17. COL17-negative skin in human junctional epidermolysis bullosa showed a distinct epidermal pattern from COL17-positive skin that resulted from revertant mosaicism. These results demonstrate that COL17 contributes to defining mouse tail scale shapes and human skin microtopography. Our study sheds light on the role of the SC niche in tissue pattern formation.

Detection of revertant mosaicism in epidermolysis bullosa through Cas9-targeted long-read sequencing.
Ken Natsuga, Yoshikazu Furuta, Shota Takashima, Takuma Nohara, Hideyuki Kosumi, Yosuke Mai, Hideaki Higashi, Hideyuki Ujiie
Human mutation, 43, 4, 529, 536, 2022年04月, ［国際誌］
英語, 研究論文（学術雑誌）, Revertant mosaicism (RM) is a phenomenon in which inherited mutations are spontaneously corrected in somatic cells. RM occurs in some congenital skin diseases, but genetic validation of RM in clinically revertant skin has been challenging, especially when homologous recombination (HR) is responsible for RM. Here, we introduce nanopore Cas9-targeted sequencing (nCATS) for identifying HR in clinically revertant skin. We took advantage of compound heterozygous COL7A1 mutations in a patient with recessive dystrophic epidermolysis bullosa who showed revertant skin spots. Cas9-mediated enrichment of genomic DNA (gDNA) covering the two mutation sites (>8 kb) in COL7A1 and subsequent MinION sequencing successfully detected intragenic crossover in the epidermis of the clinically revertant skin. This method enables the discernment of haplotypes of up to a few tens of kilobases of gDNA. Moreover, it is devoid of polymerase chain reaction amplification, which can technically induce recombination. We, therefore, propose that nCATS is a powerful tool for understanding complicated gene modifications, including RM.

成人栄養障害型表皮水疱症患者を対象としたMuse細胞製品CL2020の国内1/2相試験 52週までの安全性の検討　　　　　　　　　　　　　　　
藤田 靖幸, 野原 拓馬, 高島 翔太, 夏賀 健, 中村 秀樹, 清水 宏, 足立 太起, 吉田 憲司, 石河 晃, 新熊 悟, 武市 拓也, 秋山 真志, 和田 理
日本皮膚科学会雑誌, 132, 3, 510, 510, (公社)日本皮膚科学会, 2022年03月
日本語

Safety and dose-sparing effect of Japanese encephalitis vaccine administered by microneedle patch in uninfected, healthy adults (MNA-J): a randomised, partly blinded, active-controlled, phase 1 trial.
Hiroaki Iwata, Kosuke Kakita, Keisuke Imafuku, Shota Takashima, Naoya Haga, Yasuyuki Yamaguchi, Kenji Taguchi, Takayoshi Oyamada
The Lancet. Microbe, 3, 2, e96-e104, 2022年02月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: It is unclear whether microneedle vaccinations of Japanese encephalitis virus can induce sufficient neutralising antibodies and reduce the amount of vaccine needed. We aimed to assess the safety and dose-sparing effect of a microneedle vaccine patch against Japanese encephalitis in healthy individuals who are naive to both the vaccine and natural infection. METHODS: The MNA-J study was a randomised, partly blinded, active-controlled, phase 1 clinical trial at Hokkaido University (Sapporo, Japan) that enrolled healthy adults aged 20-34 years with no history of Japanese encephalitis vaccination nor of infection as confirmed by seronegativity. We excluded individuals who had been infected with or vaccinated against Japanese encephalitis. Eligible participants were randomly assigned (1:1:1) to one of three groups to receive inactivated Japanese encephalitis vaccine administered twice, 3 weeks apart, by either 2·5 μg per injection by subcutaneous injection, 0·63 μg per patch by high-dose microneedle array (MNA-25%), or 0·25 μg per patch by low-dose microneedle array (MNA-10%). The randomisation sequence, using stratification by cohort and blocks of six, was computer-generated by a statistician who was unaware of group assignment. After administration, the remaining amount of unadministered vaccine was measured by ELISA and calculated as the delivered amount of vaccine. The primary outcome was the neutralising antibody titre at day 42 after first immunisation. Successful seroconversion was defined as post-vaccination titres of 1·3 (log10) or higher in individuals whose pre-vaccination titres had been less than 1 (log10). This study is registered with the Japan Registry of Clinical Trials (s011190004). FINDINGS: Between Aug 31 and Sept 2, 2019, 39 participants were enrolled and each was randomly assigned to a group (n=13 per group). No serious adverse events were observed. All participants in the microneedle array groups had a localised erythematous reaction. The amount of vaccine delivered by microneedle array to each participant was 0·63-1·15 μg (50-92%) of the full 1·26 μg for the MNA-25% group and 0·25-0·41 μg (51-84%) of the full 0·50 μg for the MNA-10% group. All participants demonstrated seroconversion at day 42, and the mean titres (log10) were 2·55 for MNA-25%, 2·04 for MNA-10%, and 2·08 for subcutaneous injection. INTERPRETATION: A microneedle patch of the Japanese encephalitis vaccine is safe, well tolerated, and immunogenically effective. The dose-sparing effect suggests a significant potential to reduce the amount of immunogens needed. However, improved delivery is needed to make it more tolerable and user friendly. FUNDING: FUJIFILM.

表皮下水疱は毛包の成長を犠牲にして治癒する　　　　　　　　　　　　　　　
藤村 悠, 高島 翔太, 中村 秀樹, 小住 英之, 王 禹楠, 眞井 洋輔, 氏家 英之, 岩田 浩明, 西江 渉, 清水 宏, 夏賀 健, 渡邉 美佳, 大野 航太, 小林 康明, 長山 雅晴, Andrea Lauria, Valentina Proserpio, Salvatore Oliviero, Giacomo Donati
日本皮膚科学会雑誌, 131, 9, 2071, 2071, (公社)日本皮膚科学会, 2021年08月
日本語

Hair follicle stem cell progeny heal blisters while pausing skin development.
Yu Fujimura, Mika Watanabe, Kota Ohno, Yasuaki Kobayashi, Shota Takashima, Hideki Nakamura, Hideyuki Kosumi, Yunan Wang, Yosuke Mai, Andrea Lauria, Valentina Proserpio, Hideyuki Ujiie, Hiroaki Iwata, Wataru Nishie, Masaharu Nagayama, Salvatore Oliviero, Giacomo Donati, Hiroshi Shimizu, Ken Natsuga
EMBO reports, 22, 7, e50882, 2021年07月05日, ［国際誌］
英語, 研究論文（学術雑誌）, Injury in adult tissue generally reactivates developmental programs to foster regeneration, but it is not known whether this paradigm applies to growing tissue. Here, by employing blisters, we show that epidermal wounds heal at the expense of skin development. The regenerated epidermis suppresses the expression of tissue morphogenesis genes accompanied by delayed hair follicle (HF) growth. Lineage tracing experiments, cell proliferation dynamics, and mathematical modeling reveal that the progeny of HF junctional zone stem cells, which undergo a morphological transformation, repair the blisters while not promoting HF development. In contrast, the contribution of interfollicular stem cell progeny to blister healing is small. These findings demonstrate that HF development can be sacrificed for the sake of epidermal wound regeneration. Our study elucidates the key cellular mechanism of wound healing in skin blistering diseases.

A case of non-bullous pemphigoid induced by IgG4 autoantibodies targeting BP230.
N Yoshimoto, S Takashima, T Kawamura, E Inamura, T Sugai, I Ujiie, K Izumi, K Natsuga, W Nishie, H Shimizu, H Ujiie
Journal of the European Academy of Dermatology and Venereology : JEADV, 35, 4, e282-e285, 2021年04月, ［国際誌］
英語

A case of vesiculobullous adult T-cell leukemia/lymphoma with a poor prognosis.
Takuya Kawamura, Shinya Kitamura, Yosuke Mai, Tatsuro Sugai, Shota Takashima, Wataru Nishie, Takuya Maeda, Teruki Yanagi
The Journal of dermatology, 48, 4, e196-e197, 2021年04月, ［国際誌］
英語

Intravenous allogeneic multilineage-differentiating stress-enduring cells in adults with dystrophic epidermolysis bullosa: a phase 1/2 open-label study.
Y Fujita, T Nohara, S Takashima, K Natsuga, M Adachi, K Yoshida, S Shinkuma, T Takeichi, H Nakamura, O Wada, M Akiyama, A Ishiko, H Shimizu
Journal of the European Academy of Dermatology and Venereology : JEADV, 2021年03月03日, ［国際誌］
英語

Dominance of Methicillin-Resistant Staphylococcus aureus in a Japanese Infant with Recessive Dystrophic Epidermolysis Bullosa.
Makoto Kondo, Shota Takashima, Hiroyuki Goto, Koji Habe, Ken Natsuga, Keiichi Yamanaka
Case reports in dermatology, 13, 2, 278, 281, 2021年, ［国際誌］
英語, A male infant had the very fragile skin and easily formed bullas by rubbing and scratching from his birth. He was diagnosed with severe recessive dystrophic epidermolysis bullosa (RDEB) due to the lack of type VII collagen by performing an immunofluorescence mapping method from a skin biopsy specimen of the patient's bulla. We analyzed the skin microbiome using next-generation sequencer. The species from the patient's skin revealed the dominance of Staphylococcus aureus (S. aureus) similar to the reports from Austria and Chile severe RDEB patients, and these results are same as the pattern isolated from the skin of atopic dermatitis (AD) patients with flares. The interaction of microbiome and skin microenvironment may be similar between RDEB and AD worldwide.

Intravenous Injection of Muse Cells as a Potential Therapeutic Approach for Epidermolysis Bullosa.
Yasuyuki Fujita, Miho Komatsu, San Eun Lee, Yoshihiro Kushida, Chihiro Nakayama-Nishimura, Wakana Matsumura, Shota Takashima, Satoru Shinkuma, Toshifumi Nomura, Naoya Masutomi, Makoto Kawamura, Mari Dezawa, Hiroshi Shimizu
The Journal of investigative dermatology, 141, 1, 198, 202, 2021年01月, ［国際誌］
英語, 研究論文（学術雑誌）

Type XVII collagen interacts with the aPKC-PAR complex and maintains epidermal cell polarity.
Mika Watanabe, Hideyuki Kosumi, Shin-Ichi Osada, Shota Takashima, Yunan Wang, Wataru Nishie, Tsukasa Oikawa, Tomonori Hirose, Hiroshi Shimizu, Ken Natsuga
Experimental dermatology, 30, 1, 62, 67, 2021年01月, ［国際誌］
英語, 研究論文（学術雑誌）, Type XVII collagen (COL17) is a transmembrane protein expressed in the basal epidermis. COL17 serves as a niche for epidermal stem cells, and although its reduction has been implicated in altering cell polarity and ageing of the epidermis, it is unknown how COL17 affects epidermal cell polarity. Here, we uncovered COL17 as a binding partner of the aPKC-PAR complex, which is a key regulating factor of cell polarity. Immunoprecipitation-immunoblot assay and protein-protein binding assay revealed that COL17 interacts with aPKC and PAR3. COL17 deficiency or epidermis-specific aPKCλ deletion destabilized PAR3 distribution in the epidermis, while aPKCζ knockout did not. Asymmetrical cell division was pronounced in COL17-null neonatal paw epidermis. These results show that COL17 is pivotal for maintaining epidermal cell polarity. Our study highlights the previously unrecognized role of COL17 in the basal keratinocytes.

Calcinosis cutis in self-healing dominant dystrophic epidermolysis bullosa.
Shota Takashima, Yasuyuki Fujita, Satoru Shinkuma, Satoko Shimizu, Tomoka Hasegawa, Norio Amizuka, Hiroshi Shimizu, Ken Natsuga
The Journal of dermatology, 47, 12, e457-e458, 2020年12月, ［国際誌］
英語

Two Cases of Interleukin-7-Deficient Generalized Verrucosis.
Hideyuki Kosumi, Ken Natsuga, Shota Takashima, Toshinari Miyauchi, Yi-Ting Huang, Toshifumi Nomura, Teruki Yanagi, Hsin-Yu Huang, Frank Po-Chao Chiu, Peng-Chieh Chen, Chao-Kai Hsu, Hiroshi Shimizu
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 71, 6, 1561, 1563, 2020年09月12日, ［国際誌］
英語, 研究論文（学術雑誌）, We report 2 generalized verrucosis (GV) patients homozygous for a novel mutation in the start codon of IL7. Unlike the previous report in which IL-7 deficiency accompanied CD4 T lymphocytopenia, circulating CD4 T cells were not depleted in one of our patients, suggesting a GV pathogenesis other than poor T-cell development.

Electron Microscopic and Immunohistochemical Findings of the Epidermal Basement Membrane in Two Families with Nail-patella Syndrome.
Satoru Shinkuma, Hideki Nakamura, Manami Maehara, Shota Takashima, Toshifumi Nomura, Yasuyuki Fujita, Satoshi Hasegawa, Kazuko C Sato-Matsumura, Riichiro Abe, Hiroshi Shimizu
Acta dermato-venereologica, 99, 12, 1110, 1115, 2019年11月01日, ［国際誌］
英語, 研究論文（学術雑誌）, Nail-patella syndrome is an autosomal dominant disorder characterized by nail dysplasia and skeletal anomaly. Some patients have been shown to have ultrastructural abnormalities of the glomerular basement membrane that result in nephrosis. However, little has been reported on the epidermal basement membrane in this condition. This paper reports 2 families with nail-patella syndrome. Direct sequencing analysis of LMX1B revealed that family 1 and family 2 were heterozygous for the mutations c.140-1G>C and c.326+1G>C, respectively. To evaluate the epidermal basement membrane zone, ultrastructural and immunohistochemical analyses were performed using skin specimens obtained from the dorsal thumb. Electron microscopy showed intact hemidesmosomes, lamina lucida, lamina densa, and anchoring fibrils. Immunofluorescence studies with antibodies against components of the epidermal basement membrane zone revealed a normal expression pattern among the components, including type IV collagen. These data suggest that nail dysplasia in patients with nail-patella syndrome is not caused by structural abnormalities of the epidermal basement membrane.

Cultured Epidermal Autografts from Clinically Revertant Skin as a Potential Wound Treatment for Recessive Dystrophic Epidermolysis Bullosa.
Wakana Matsumura, Yasuyuki Fujita, Satoru Shinkuma, Shotaro Suzuki, Saki Yokoshiki, Hideki Goto, Hiroshi Hayashi, Kota Ono, Masukazu Inoie, Shota Takashima, Chihiro Nakayama, Toshifumi Nomura, Hideki Nakamura, Riichiro Abe, Norihiro Sato, Hiroshi Shimizu
The Journal of investigative dermatology, 139, 10, 2115, 2124, 2019年10月, ［国際誌］
英語, 研究論文（学術雑誌）, Inherited skin disorders have been reported recently to have sporadic normal-looking areas, where a portion of the keratinocytes have recovered from causative gene mutations (revertant mosaicism). We observed a case of recessive dystrophic epidermolysis bullosa treated with cultured epidermal autografts (CEAs), whose CEA-grafted site remained epithelized for 16 years. We proved that the CEA product and the grafted area included cells with revertant mosaicism. Based on these findings, we conducted an investigator-initiated clinical trial of CEAs from clinically revertant skin for recessive dystrophic epidermolysis bullosa. The donor sites were analyzed by genetic analysis, immunofluorescence, electron microscopy, and quantification of the reverted mRNA with deep sequencing. The primary endpoint was the ulcer epithelization rate per patient at 4 weeks after the last CEA application. Three patients with recessive dystrophic epidermolysis bullosa with 8 ulcers were enrolled, and the epithelization rate for each patient at the primary endpoint was 87.7%, 100%, and 57.0%, respectively. The clinical effects were found to persist for at least 76 weeks after CEA transplantation. One of the three patients had apparent revertant mosaicism in the donor skin and in the post-transplanted area. CEAs from clinically normal skin are a potentially well-tolerated treatment for recessive dystrophic epidermolysis bullosa.

Efficient Gene Reframing Therapy for Recessive Dystrophic Epidermolysis Bullosa with CRISPR/Cas9.
Shota Takashima, Satoru Shinkuma, Yasuyuki Fujita, Toshifumi Nomura, Hideyuki Ujiie, Ken Natsuga, Hiroaki Iwata, Hideki Nakamura, Artem Vorobyev, Riichiro Abe, Hiroshi Shimizu
The Journal of investigative dermatology, 139, 8, 1711, 1721, 2019年08月, ［国際誌］
英語, 研究論文（学術雑誌）, The clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system induces site-specific double-strand breaks, which stimulate cellular DNA repair through either the homologous recombination or non-homologous end-joining pathways. The non-homologous end-joining pathway, which is activated more frequently than homologous recombination, is prone to introducing small insertions and/or deletions at the double-strand break site, leading to changes in the reading frame. We hypothesized that the non-homologous end-joining pathway is applicable to genetic diseases caused by a frameshift mutation through restoration of the reading frame. Recessive dystrophic epidermolysis bullosa is a hereditary skin disorder caused by mutations in COL7A1. In this study, we applied gene reframing therapy to a recurrent frameshift mutation, c.5819delC, in COL7A1, which results in a premature termination codon. CRISPR/Cas9 targeting this specific mutation site was delivered to recessive dystrophic epidermolysis bullosa patient fibroblasts. After genotyping a large collection of gene-edited fibroblast clones, we identified a significant number (17/50) of clones in which the frameshift in COL7A1 was restored. The reframed COL7 was functional, as shown by triple-helix formation assay in vitro, and was correctly distributed in the basement membrane zone in mice. Our data suggest that mutation site-specific non-homologous end-joining might be a highly efficient gene therapy for inherited disorders caused by frameshift mutations.

Image Gallery: Multiple localized lipoatrophy in recessive dystrophic epidermolysis bullosa.
T Nohara, Y Fujita, S Takashima, K Natsuga, H Shimizu
The British journal of dermatology, 180, 3, e64, 2019年03月, ［国際誌］
英語

Novel COL7A1 mutation in a family with bullous dermolysis of the newborn: Phenotypic variability associated with a COL7A1 mutation within the same family.
Shota Takashima, Satoru Shinkuma, Yasuyuki Fujita, Ken Natsuga, Toshifumi Nomura, Tokimasa Hida, Shuku Ishikawa, Hideki Nakamura, Riichiro Abe, Hiroshi Shimizu
The Journal of dermatology, 45, 9, e260-e261, 2018年09月, ［国際誌］
英語

The development of induced pluripotent stem cell-derived mesenchymal stem/stromal cells from normal human and RDEB epidermal keratinocytes.
Chihiro Nakayama, Yasuyuki Fujita, Wakana Matsumura, Inkin Ujiie, Shota Takashima, Satoru Shinkuma, Toshifumi Nomura, Riichiro Abe, Hiroshi Shimizu
Journal of dermatological science, 91, 3, 301, 310, 2018年09月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Epidermolysis bullosa (EB) is a group of hereditary disorders caused by mutations in the genes encoding structural molecules of the dermal-epidermal junction (DEJ). Cell-based therapies such as allogeneic mesenchymal stem/stromal cell (MSC) transplantation have recently been explored for severe EB types, such as recessive dystrophic EB (RDEB). However, hurdles exist in current MSC-based therapies, such as limited proliferation from a single cell source and limited cell survival due to potential allogenic rejection. OBJECTIVES: We aimed to develop MSCs from keratinocyte-derived induced pluripotent stem cells (iPSCs). METHODS: Keratinocyte-derived iPSCs (KC-iPSCs) of a healthy human and an RDEB patient were cultured with activin A, 6-bromoindirubin-3'-oxime and bone morphogenetic protein 4 to induce mesodermal lineage formation. These induced cells were subjected to immunohistochemical analysis, flow cytometric analysis and RNA microarray analysis in vitro, and were injected subcutaneously and intravenously to wounded immunodeficient mice to assess their wound-healing efficacy. RESULTS: After their induction, KC-iPSC-induced cells were found to be compatible with MSCs. Furthermore, with the subcutaneous and intravenous injection of the KC-iPSC-induced cells into wounded immunodeficient mice, human type VII collagen was detected at the DEJ of epithelized areas. CONCLUSIONS: We successfully established iPSC-derived MSCs from keratinocytes (KC-iPSC-MSCs) of a normal human and an RDEB patient. KC-iPSC-MSCs may have potential in therapies for RDEB.

Appearance of antidesmocollin 1 autoantibodies leading to a vegetative lesion in a patient with pemphigus vulgaris.
Y Yamaguchi, S Shinkuma, N Ishii, S Takashima, K Natsuga, H Ujiie, H Iwata, T Nomura, Y Fujita, A Hamasaka, K Hamasaka, T Hashimoto, H Shimizu
The British journal of dermatology, 178, 1, 294, 295, 2018年01月, ［査読有り］, ［国際誌］
英語

Multiple Hyperpigmented Macules in a Child.
Yuka Maya, Shota Takashima, Mitsuhito Ota
JAMA, 318, 15, 1493, 1494, 2017年10月17日, ［国際誌］
英語

A case of recessive dystrophic epidermolysis bullosa with a novel c.6885_6898del14 mutation in the COL7A1 gene.
Satoru Shinkuma, Tae Masunaga, Saori Miyawaki, Shota Takashima, Ken Natsuga, Toshifumi Nomura, Yasuyuki Fujita, Hideki Nakamura, Hiroshi Shimizu
Journal of dermatological science, 88, 1, 139, 141, 2017年10月, ［国際誌］
英語

The first familial cases of epidermolysis bullosa simplex, generalized severe with p.Asn176Ser in KRT5 revealing the clinical chronology
T. Sugai, S. Shinkuma, K. Inafuku, S. Takashima, T. Nomura, Y. Fujita, H. Nakamura, H. Shimizu
JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY, 31, 5, e251, e253, WILEY, 2017年05月
英語

RNA recognition motif of LEMD3 as a key player in the pathogenesis of Buschke-Ollendorff syndrome.
Shota Takashima, Yasuyuki Fujita, Shotaro Suzuki, Nao Saito, Satoru Shinkuma, Toshifumi Nomura, Hiroshi Shimizu
Journal of dermatological science, 81, 3, 205, 8, 2016年03月, ［国際誌］
英語

Fasciitis-panniculitis Syndromeの1例
白戸 貴久, 藤田 靖幸, 高島 翔太, 齋藤 奈央, 乃村 俊史, 堀田 哲也, 清水 宏
皮膚科の臨床, 58, 2, 232, 235, 金原出版(株), 2016年02月, ［査読有り］
日本語, 40歳男。1年半前より下肢の運動時制限を自覚し、徐々に四肢の硬化を認めたため当科を受診した。受診時、両手背から前腕、足背から下腿にかけてびまん性に皮膚が硬化し、前腕では表在静脈に沿って線状に陥凹していた。造影MRIで両下腿筋膜が高信号を呈していた。病理組織学的所見より、fasciitis-panniculitis syndromeと診断された。診断後はプレドニゾロンの内服を開始したところ、硬化と可動域制限は徐々に改善した。

Creeping lymphangitis.
Shota Takashima, Mitsuhito Ota
BMJ (Clinical research ed.), 351, h5416, 2015年10月13日, ［国際誌］
英語, 研究論文（学術雑誌）

An Iatrogenic Metastasis
Shota Takashima, Shunichi Okubo, Mitsuhito Ota
American Journal of Medicine, 128, 9, e15, e16, Elsevier Inc., 2015年09月01日
英語, 研究論文（学術雑誌）

An Iatrogenic Metastasis.
Shota Takashima, Shunichi Okubo, Mitsuhito Ota
The American journal of medicine, 128, 9, e15-6, 2015年09月, ［国際誌］
英語

Herpes zoster triplex.
Shota Takashima, Mitsuhito Ota
Cleveland Clinic journal of medicine, 82, 9, 579, 579, 2015年09月, ［国際誌］
英語, 研究論文（学術雑誌）

Methotrexate-induced nodulosis.
Shota Takashima, Mitsuhito Ota
CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne, 187, 10, E327, 2015年07月14日, ［国際誌］
英語, 研究論文（学術雑誌）

Pruritic Papules Following Lumbar Corset Use: A Quiz. Grover's disease.
Toshinari Miyauchi, Yasuyuki Fujita, Shota Takashima, Yusuke Morita, Shotaro Suzuki, Osamu Mizuno, Nao Saito, Toshifumi Nomura, Hiroshi Shimizu
Acta dermato-venereologica, 95, 6, 762, 3, 2015年07月, ［国際誌］
英語, 研究論文（学術雑誌）

Dermoscopic observation in adenoma of the nipple.
Shota Takashima, Yasuyuki Fujita, Toshinari Miyauchi, Toshifumi Nomura, Wataru Nishie, Hideji Hamaoka, Hiroshi Shimizu
The Journal of dermatology, 42, 3, 341, 2, 2015年03月, ［国際誌］
英語

Tumoral calcinosis in chronic renal failure.
Shota Takashima, Takashi Sakamoto, Mitsuhito Ota
The lancet. Diabetes & endocrinology, 2, 10, 852, 852, 2014年10月, ［国際誌］
英語, 研究論文（学術雑誌）

Petechial rash with parvovirus infection
Shota Takashima, Mitsuhito Ota, The BMJ, 367, 2019年
BMJ Publishing Group, 英語, 速報，短報，研究ノート等（学術雑誌）

Ocular erythema nodosum
Shota Takashima, Mitsuhito Ota, The BMJ, 366, 2019年
BMJ Publishing Group, 英語, 速報，短報，研究ノート等（学術雑誌）

Two families of nail-patella syndrome with novel splice site mutations in the LMX1B gene
S. Shinkuma, H. Nakamura, S. Takashima, T. Nomura, Y. Fujita, S. Hasegawa, K. Matsumura, H. Shimizu, R. Abe, JOURNAL OF INVESTIGATIVE DERMATOLOGY, 137, 10, S231, S231, 2017年10月
ELSEVIER SCIENCE INC, 英語, 研究発表ペーパー・要旨（国際会議）

A case of recessive dystrophic epidermolysis bullosa with a novel c.6885_6898del14 mutation
S. Shinkukma, T. Masunaga, S. Miyawaki, S. Takashima, T. Nomura, Y. Fujita, H. Nakamura, H. Shimizu, JOURNAL OF INVESTIGATIVE DERMATOLOGY, 137, 5, S87, S87, 2017年05月
ELSEVIER SCIENCE INC, 英語, 研究発表ペーパー・要旨（国際会議）

重症汎発型単純型表皮水疱症の家族例　　　　　　　　　　　　　　　
須貝 達朗, 新熊 悟, 高島 翔太, 乃村 俊史, 藤田 靖幸, 中村 秀樹, 清水 宏, 稲福 和宏, 日本皮膚科学会雑誌, 127, 2, 221, 221, 2017年02月
(公社)日本皮膚科学会, 日本語

新規frame shift変異を認めたBuschke-Ollendorff症候群の1家系　　　　　　　　　　　　　　　
高島 翔太, 藤田 靖幸, 鈴木 翔多郎, 齋藤 奈央, 新熊 悟, 乃村 俊史, 清水 宏, 日本臨床皮膚科医会雑誌, 32, 3, 432, 432, 2015年05月
日本臨床皮膚科医会, 日本語

Fasciitis-panniculitis syndromeの1例　　　　　　　　　　　　　　　
白戸 貴久, 藤田 靖幸, 高島 翔太, 齋藤 奈央, 乃村 俊史, 清水 宏, 堀田 哲也, 日本皮膚科学会雑誌, 125, 6, 1268, 1268, 2015年05月
(公社)日本皮膚科学会, 日本語

LEMD3遺伝子に新規フレームシフト変異を認めたBuschke-Ollendorff症候群の1家系　　　　　　　　　　　　　　　
高島 翔太, 藤田 靖幸, 鈴木 翔多朗, 齋藤 奈央, 新熊 悟, 乃村 俊史, 清水 宏, 日本皮膚科学会雑誌, 125, 3, 447, 447, 2015年03月
(公社)日本皮膚科学会, 日本語

ケラチン9遺伝子変異を認めたepidermolytic palmoplantar keratodermaの1例　　　　　　　　　　　　　　　
高島 翔太, 乃村 俊史, 鈴木 翔多朗, 藤村 悠, 中里 信一, 夏賀 健, 佐藤 英嗣, 阿部 理一郎, 清水 宏, 日本皮膚科学会雑誌, 124, 4, 792, 792, 2014年04月
(公社)日本皮膚科学会, 日本語

表皮水疱症の創傷治癒遅延因子の同定とその克服
科学研究費助成事業
2023年04月01日 - 2026年03月31日
夏賀 健, 眞井 洋輔, 長山 雅晴, 高島 翔太
日本学術振興会, 基盤研究(B), 北海道大学, 23H02928

エクソンスキッピング誘導による劣性栄養障害型表皮水疱症の病態理解と治療応用
科学研究費助成事業
2023年04月01日 - 2025年03月31日
高島 翔太
日本学術振興会, 若手研究, 北海道大学, 23K15276

スプライシングによる表皮基底膜タンパクの多様性とその意義の解明　　　　　　　　　　　　　　　
基礎医学研究費（資生堂寄付）
2024年04月 - 2025年03月
日本皮膚科学会

高純度ベタニンのスキンケアへの応用　　　　　　　　　　　　　　　
イノベーション創出研究支援事業（産学連携創出補助金)
2023年07月 - 2024年03月
ノーステック財団, 北海道大学

スプライシングが制御する表皮角化細胞分化機構の解明　　　　　　　　　　　　　　　
研修奨励
2023年04月 - 2024年03月
上原記念生命科学財団

選択的スプライシングが制御する表皮角化細胞分化機構と皮膚疾患の病態解明　　　　　　　　　　　　　　　
研究助成（奨励）
2023年04月
秋山記念生命科学振興財団