研究者詳細 - 奥野　凌輔

写真a

オクノ　リョウスケ

奥野　凌輔

OKUNO Ryosuke

所属

大学院医学系研究科メナード協同研究講座特任助教

学位 1

修士（理学）（ 2015年3月名古屋大学）

学位の先頭へ▲

論文 10

Genome-wide association studies in the Japanese population identified genetic loci and target gene associated with epidermal turnover

Okuno, R; Inoue, Y; Hasebe, Y; Igarashi, T; Kawagishi-Hotta, M; Yamada, T; Hasegawa, S

EXPERIMENTAL DERMATOLOGY 32 巻 ( 10 ) 頁： 1856 - 1863 2023年10月

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記述言語：英語出版者・発行元：Experimental Dermatology

The epidermis is an essential organ for life by retaining water and as a protective barrier. The epidermis is maintained through metabolism, in which basal cells produced from epidermal stem cells differentiate into spinous cells, granular cells and corneocytes, and are finally shed from the epidermal surface. This is epidermal turnover, and with aging, there is a decline in epidermis function. Other factors that may affect epidermal turnover include ultraviolet damage and genetic factors. These genetic factors are of particular interest as little is known. Although recent skin-focused genome-wide association studies (GWAS) have been conducted, the genetic regions associated with epidermal turnover are almost uninvestigated. Therefore, we conducted a GWAS on epidermal turnover in the Japanese population, using the corneocyte area, which correlates to the rate of epidermal turnover, as an indicator. As a result, rs2278431 (p = 1.29 × 10−7) in 19q13.2 was associated with corneocyte size. Furthermore, eQTL analysis suggested that rs2278431 was related to the SPINT2 gene. In addition, SPINT2 knockdown studies using epidermal keratinocytes revealed that SPINT2 is involved in keratinocyte proliferation and in corneocyte size regulation in reconstructed epidermis. These results suggest that rs2278431 is involved in the expression of SPINT2 and affects epidermal turnover.

DOI： 10.1111/exd.14908

Web of Science

Scopus

PubMed
A genome-wide association study identified a genetic variant associated with hair thinning in Japanese women

Okuno, R; Igarashi, T; Hasebe, Y; Kawagishi-Hotta, M; Hasegawa, S

JOURNAL OF COSMETIC DERMATOLOGY 22 巻 ( 9 ) 頁： 2616 - 2618 2023年9月

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記述言語：英語出版者・発行元：Journal of Cosmetic Dermatology

DOI： 10.1111/jocd.15740

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PubMed
Identification of mitochondrial genetic variants associated with human corneocyte size in Japanese women

Inoue, Y; Igarashi, T; Hasebe, Y; Kawagishi-Hotta, M; Okuno, R; Yamada, T; Hasegawa, S

EXPERIMENTAL DERMATOLOGY 31 巻 ( 12 ) 頁： 1944 - 1948 2022年12月

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記述言語：英語出版者・発行元：Experimental Dermatology

Mitochondria have their own DNA (mtDNA). Genetic variants are likely to accumulate in mtDNA, and its base substitution rate is known to be very fast, 10–20 times faster than that of nuclear DNA. For this reason, mtSNPs (mitochondrial genome single nucleotide polymorphisms) are frequently detected in mtDNA. Several thousands of copies of mtDNA are considered to be present in a cell, and variants that have occurred in mtDNA are expected to markedly affect the intracellular energy production system and ROS (reactive oxygen species) kinetics. Therefore, recently, mtSNPs have come to be considered very important as a determinant of the individual constitution such as the life-span and disease susceptibility. In this study, we searched for mtSNPs that affect the individual corneocyte size using samples from 358 Japanese women. As a result, mtSNPs 10609C and 12406A were found to be significantly related to the corneocyte size in the outermost layer of the epidermis. There have been a large number of reports concerning the association between mtSNPs and individual constitution, but little evaluation of their relationships with epidermal properties has been made. The results of the present study first suggested that mtSNPs may affect the epidermal properties in Japanese women.

DOI： 10.1111/exd.14673

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PubMed
Genome-wide association studies in Japanese women identified genetic loci associated with wrinkles and sagging

Okuno, R; Inoue, Y; Hasebe, Y; Igarashi, T; Kawagishi-Hotta, M; Yamada, T; Hasegawa, S

EXPERIMENTAL DERMATOLOGY 31 巻 ( 9 ) 頁： 1411 - 1420 2022年9月

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記述言語：英語出版者・発行元：Experimental Dermatology

Wrinkles and sagging are caused by various factors, such as ultraviolet rays; however, recent findings demonstrated that some individuals are genetically predisposed to these phenotypes of skin aging. The contribution of single nucleotide polymorphisms (SNPs) to the development of wrinkles and sagging has been demonstrated in genome-wide association studies (GWAS). However, these findings were mainly obtained from European and Chinese populations. Limited information is currently available on the involvement of SNPs in the development of wrinkles and sagging in a Japanese population. Therefore, we herein performed GWAS on wrinkles at the outer corners of the eyes and nasolabial folds in 1041 Japanese women. The results obtained revealed that 5 SNPs (19p13.2: rs2303098 (p = 3.39 × 10−8), rs56391955 (p = 3.39 × 10−8), rs67560822 (p = 3.50 × 10−8), rs889126 (p = 3.78 × 10−8), rs57490083 (p = 3.99 × 10−8)) located within the COL5A3 gene associated with wrinkles at the outer corners of the eyes. Regarding nasolabial folds, 8q24.11 (rs4876369; p = 1.05 × 10−7, rs6980503; p = 1.25 × 10−7, rs61027543; p = 1.25 × 10−7, rs16889363; p = 1.38 × 10−7) was suggested to be associated with RAD21 gene expression. These SNPs have not been reported in other populations, and were first found in Japanese women population. These SNPs may be used as markers to examine the genetic predisposition of individuals to wrinkles and sagging.

DOI： 10.1111/exd.14612

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PubMed
Analysis of the effect of daily stress on the skin and search for genetic loci involved in the perceived stress of an individual.

Inoue Y, Hasebe Y, Igarashi T, Kawagishi-Hotta M, Okuno R, Yamada T, Hasegawa S

Skin health and disease 2 巻 ( 3 ) 頁： e110 2022年9月

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記述言語：英語

DOI： 10.1002/ski2.110

PubMed
Increase in inhibin beta A/Activin-A expression in the human epidermis and the suppression of epidermal stem/progenitor cell proliferation with aging

Kawagishi-Hotta, M; Hasegawa, S; Hasebe, Y; Inoue, Y; Okuno, R; Arima, M; Iwata, Y; Sugiura, K; Akamatsu, H

JOURNAL OF DERMATOLOGICAL SCIENCE 106 巻 ( 3 ) 頁： 150 - 158 2022年6月

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記述言語：英語出版者・発行元：Journal of Dermatological Science

Background: Age-related thinning and reduced cell proliferation in the human epidermis are associated with the accumulation of senescent cells and decreases in the number and function of epidermal stem cells. Objective: This study examined the expression of INHBA/Activin-A in human epidermis and expression differences with age, and the effect of Activin-A on epidermal stem/progenitor cells. Methods: Immunohistochemical staining was used to analyze age-related changes in the expression of INHBA/Activin-A in the epidermal tissue of young and old subjects. Epidermal INHBA/Activin-A expression levels, epidermal morphology, and the number of epidermal stem/progenitor cells or proliferating cells were investigated using older abdominal skin samples. The effects of Activin-A on the development of a three-dimensional (3D) reconstructed epidermis and cell proliferation were also assessed. Results: INHBA/Activin-A expression levels in the human epidermis increased with age, although they varied among individuals. In the epidermis of older abdominal skin samples, INHBA/Activin-A expression levels negatively correlated with epidermal thickness, the rete ridge depth and the interdigitation index. The proportion of epidermal stem/progenitor cells and proliferating cells decreased with increases in INHBA/Activin-A expression levels. Activin-A had no effect on the differentiation of keratinocytes in the 3D-reconstructed epidermis; however, thinning of the 3D epidermis was noted. Moreover, the addition of Activin-A inhibited the proliferation of epidermal stem/progenitor cells in a concentration-dependent manner. Conclusions: Age-related increased in INHBA/Activin-A expression levels were observed in the human epidermis, and may contribute to epidermal thinning and decreases in the number of epidermal stem/progenitor cells and proliferative activity.

DOI： 10.1016/j.jdermsci.2022.05.001

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PubMed
Search for genetic loci involved in the constitution and skin type of a Japanese women using a genome-wide association study 査読有り

Inoue, Y; Hasebe, Y; Igarashi, T; Kawagishi-Hotta, M; Okuno, R; Yamada, T; Hasegawa, S

EXPERIMENTAL DERMATOLOGY 30 巻 ( 12 ) 頁： 1787 - 1793 2021年12月

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記述言語：英語出版者・発行元：Experimental Dermatology

The constitution and skin type of individuals are influenced by various factors. Recently, the influence of genetic predispositions on these has been emphasized. To date, genome-wide association studies (GWAS) have shown several single nucleotide polymorphisms (SNPs) that affect individual's constitution and skin type. However, these studies have mainly focused on the Caucasian population, and only a few association analyses with the constitution and skin type of individuals involving a Japanese population have been conducted. In this study, we conducted a GWAS analysis of 9 phenotypes regarding the constitution or skin type of 1108 Japanese women based on a questionnaire. As a result, in addition to SNPs known to be involved in phenotypes in the past, we discovered new SNPs and genetic regions related to darkness of pigmented spots, skin flushing, frequency of rough skin and responsiveness to cosmetics.

DOI： 10.1111/exd.14430

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PubMed
Establishment of Three Types of Immortalized Human Skin Stem Cell Lines Derived from the Single Donor

Inoue, Y; Hasegawa, S; Hasebe, Y; Kawagishi-Hotta, M; Okuno, R; Yamada, T; Adachi, H; Miyachi, K; Ishii, Y; Sugiura, K; Akamatsu, H

BIOLOGICAL & PHARMACEUTICAL BULLETIN 44 巻 ( 10 ) 頁： 1403 - 1412 2021年10月

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記述言語：英語出版者・発行元：Biological and Pharmaceutical Bulletin

Currently, human-skin derived cell culture is a basic technique essential for dermatological research, cellular engineering research, drug development, and cosmetic development. But the number of donors is limited, and primary cell function reduces through cell passage. In particular, since adult stem cells are present in a small amount in living tissues, it has been difficult to obtain a large amount of stem cells and to stably culture them. In this study, skin derived cells were isolated from the epidermis, dermis, and adipose tissue collected from single donor, and immortalization was induced through gene transfer. Subsequently, cell lines that could be used as stem cell models were selected using the differentiation potential and the expression of stem cell markers as indices, and it was confirmed that these could be stably cultured. The immortalized cell lines established in this study have the potential to be applied not only to basic dermatological research but also to a wide range of fields such as drug screening and cell engineering.

DOI： 10.1248/bpb.b21-00058

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CiNii Research
加齢によるIGFBP-4の増加は皮膚の老化を引き起こす

奥野凌輔, 田中浩, 長谷川靖司, 中田悟

日本化粧品技術者会誌 54 巻 ( 1 ) 頁： 33 - 41 2020年3月

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記述言語：日本語出版者・発行元：日本化粧品技術者会

IGF-1（インスリン様成長因子1）は細胞の増殖や分化にさまざまな役割を果たしている。皮膚においてはケラチノサイトの増殖促進効果や線維芽細胞におけるコラーゲン産生促進効果，分解抑制効果などを有することがしられている。加齢によってIGF-1 の産生量が減少することによりIGF-1 の機能発現が低下することはよくしられているが，IGF-1 を受容する細胞側の加齢変化は十分には明らかになっていない。そこで本研究では，皮膚細胞におけるIGF-1 機能調節能の加齢に伴う変化を検討した。老化した細胞においては，IGF-1 を添加してもケラチノサイトの増殖促進効果，線維芽細胞におけるコラーゲンの代謝変化誘導効果は低下した。また，いずれの細胞でも，IGF-1 の機能を抑制することが報告されているIGFBP-4（IGF 結合タンパク質4）の発現量が老化によって有意に増加した。さらに，IGFBP-4 をIGF-1 と同時に各細胞に添加するとIGF-1 によるケラチノサイトの増殖促進効果，線維芽細胞におけるコラーゲン産生促進効果，分解抑制効果がいずれも抑制された。以上の結果から，加齢によりIGF-1 の機能発現が低下する原因の1 つとして，IGF-1 を受容する細胞側におけるIGFBP-4 産生の増加を介したIGF-1 シグナリングの低下が考えられた。

DOI： 10.5107/sccj.54.33

CiNii Research
Na+/H+ Exchanger 1（NHE1）の機能低下は皮膚の保湿およびバリア機能に影響する査読有り

村上祐子, 奥野凌輔, 田中浩, 長谷川靖司, 八代洋一, 中田悟

日本香粧品学会誌 43 巻 ( 1 ) 頁： 1 - 7 2019年3月

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記述言語：日本語出版者・発行元：日本香粧品学会

Recently, it has become clear that Na+/H+ exchanger 1 (NHE1) plays an important role in the acidification of skin surface. NHE1 exists on the cell membrane of keratinocytes and regulates intracellular pH by effectively extruding H+ ions from intracellular compartments in exchange for external sodium ions, which also controls the acidification of extracellular microdomains and, consequently, was suggested to contributes to skin surface pH. Our previous study using human skin suggested that NHE1 protein amount, skin surface pH, and the onset of rough skin are related to each other. In this study, we investigated how NHE1 participated in skin surface pH, and the water holding capacity and the barrier function of the stratum corneum in human keratinocytes. A NHE1 activator significantly increased the mRNA expression of filaggrin (FLG) and serine palmitoyl transferase (SPT), a ceramide synthesis enzyme, while a NHE1 inhibitor significantly decreased the mRNA expression of both. Environmental and mental stress factors decreased the NHE1 mRNA expression in human keratinocytes. Moreover, a mild acidic environment significantly decreased the FLG and SPT mRNA expression in human keratinocytes. On the basis of these results, NHE1 was suggested to play an important role in not only controlling skin surface pH but also maintaining water holding capacity and barrier function of stratum corneum. Furthermore, decreased level of NHE1 due to environmental and mental stress was assumed to decrease water holding capacity and barrier function of stratum corneum, followed by the onset of rough skin. Therefore, to improve rough skin, preventing the depression of NHE1 function was considered to be more important than mere acidification of skin surface.

DOI： 10.11469/koshohin.43.1

CiNii Research

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