Hase, Koji

写真a

Affiliation

Faculty of Pharmacy, Department of Pharmaceutical Sciences 生化学講座 (Shiba-Kyoritsu)

Position

Professor

Related Websites

External Links
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Research Areas 【 Display / hide 】

  • Life Science / Immunology

  • Life Science / Gastroenterology

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Research Keywords 【 Display / hide 】

  • Mucosal Immunology

  • Intestinal Micorobiology

  • Microfold cells

  • Inflammatory bowel disease

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Books 【 Display / hide 】

  • DOHaD 先制医療への展開

    大橋若奈，長谷耕二, 金原出版株式会社, 2023.05

    Scope: 腸内細菌叢（マイクロバイオーム）を介した母子連関,  Contact page： 58-63

  • 腸内細菌−宿主のクロストークと食事因子（日本栄養・食糧学会監修）

    山田恭央, 長谷耕二., 建帛社, 2019.05

    Scope: 炎症性腸疾患における腸内代謝物の異常とそのメカニズム. 腸内細菌−宿主のクロストークとこれを修飾する食事要因,  Contact page： 120-144

  • 腸内細菌−宿主のクロストークと食事因子（日本栄養・食糧学会監修）

    長谷耕二, 高橋大輔, 建帛社, 2019.05

    Scope: 自己免疫疾患の発症を制御する短鎖脂肪酸,  Contact page： 191-201

  • The Frontier in Life Science: 免疫・炎症病態×治療 Update

    松本龍太郎, 高橋大輔, 長谷耕二, 2019.04

    Scope: 腸管免疫学研究のフロントライン

  • ヒトマイクロバイオーム研究最前線

    長谷 耕二, （株）エヌ・ティー・エス　, 2016.03

    Scope: 腸内細菌定着と宿主エピゲノム変化

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Papers 【 Display / hide 】

  • Protective effect of mesenchymal stromal cells in diabetic nephropathy: the In vitro and In vivo role of the M-Sec-tunneling nanotubes

    Barutta F., Corbetta B., Bellini S., Gambino R., Bruno S., Kimura S., Hase K., Ohno H., Gruden G.

    Clinical Science 138 ( 23 ) 1537 - 1559 2024.12

    Research paper (scientific journal), Accepted

    　View Summary

    Mitochondrial dysfunction plays an important role in the development of podocyte injury in diabetic nephropathy (DN). Tunnelling nanotubes (TNTs) are long channels that connect cells and allow organelle exchange. Mesenchymal stromal cells (MSCs) can transfer mitochondria to other cells through the M-Sec-TNTs system. However, it remains unexplored whether MSCs can form heterotypic TNTs with podocytes, thereby enabling the replacement of diabetes-damaged mitochondria. In this study, we analysed TNT formation, mitochondrial transfer, and markers of cell injury in podocytes that were pre-exposed to diabetes-related insults and then co-cultured with diabetic or non-diabetic MSCs. Furthermore, to assess the in vivo relevance, we treated DN mice with exogenous MSCs, either expressing or lacking M-Sec, carrying fluorescent-tagged mitochondria. MSCs formed heterotypic TNTs with podocytes, allowing mitochondrial transfer, via a M-Sec-dependent mechanism. This ameliorated mitochondrial function, nephrin expression, and reduced apoptosis in recipient podocytes. However, MSCs isolated from diabetic mice failed to confer cytoprotection due to Miro-1 down-regulation. In experimental DN, treatment with exogenous MSCs significantly improved DN, but no benefit was observed in mice treated with MSCs lacking M-Sec. Mitochondrial transfer from exogenous MSCs to podocytes occurred in vivo in a M-Sec-dependent manner. These findings demonstrate that the M-Sec-TNT-mediated transfer of mitochondria from healthy MSCs to diabetes-injured podocytes can ameliorate podocyte damage. Moreover, M-Sec expression in exogenous MSCs is essential for providing renoprotection in vivo in experimental DN.

  • Intestinal epithelium dysfunctions cause IgA deposition in the kidney glomeruli of intestine-specific Ap1m2-deficient mice

    Kinashi Y., Tanaka K., Kimura S., Hirota M., Komiyama S., Shindo T., Hashiguchi A., Takahashi D., Shibata S., Karaki S.I., Ohno H., Hase K.

    EBioMedicine 106 2024.08

    Research paper (scientific journal), Last author, Corresponding author, Accepted

    　View Summary

    Background: Intestinal epithelial cells (IECs) serve as robust barriers against potentially hostile luminal antigens and commensal microbiota. Epithelial barrier dysfunction enhances intestinal permeability, leading to leaky gut syndrome (LGS) associated with autoimmune and chronic inflammatory disorders. However, a causal relationship between LGS and systemic disorders remains unclear. Ap1m2 encodes clathrin adaptor protein complex 1 subunit mu 2, which facilitates polarized protein trafficking toward the basolateral membrane and contributes to the establishment of epithelial barrier functions. Methods: We generated IEC-specific Ap1m2-deficient (Ap1m2ΔIEC) mice with low intestinal barrier integrity as an LSG model and examined the systemic impact. Findings: Ap1m2ΔIEC mice spontaneously developed IgA nephropathy (IgAN)-like features characterized by the deposition of IgA–IgG immune complexes and complement factors in the kidney glomeruli. Ap1m2 deficiency markedly enhanced aberrantly glycosylated IgA in the serum owing to downregulation and mis-sorting of polymeric immunoglobulin receptors in IECs. Furthermore, Ap1m2 deficiency caused intestinal dysbiosis by attenuating IL-22-STAT3 signaling. Intestinal dysbiosis contributed to the pathogenesis of IgAN because antibiotic treatment reduced aberrantly glycosylated IgA production and renal IgA deposition in Ap1m2ΔIEC mice. Interpretation: IEC barrier dysfunction and subsequent dysbiosis by AP-1B deficiency provoke IgA deposition in the mouse kidney. Our findings provide experimental evidence of a pathological link between LGS and IgAN. Funding: AMED, AMED-CREST, JSPS Grants-in-Aid for Scientific Research, JST CREST, Fuji Foundation for Protein Research, and Keio University Program for the Advancement of Next Generation Research Projects.

  • Sugar and arginine facilitate oral tolerance by ensuring the functionality of tolerogenic immune cell subsets in the intestine

    Nagai M., Okawa T., Nakata K., Takahashi D., Miyajima R., Shiratori H., Yamanaka D., Nakamura A., Oyama C., Takahashi S.I., Toyama-Sorimachi N., Suzuki K., Ohashi W., Dohi T., Kawamura Y.I., Hase K.

    Cell Reports 43 ( 7 )  2024.07

    Research paper (scientific journal), Last author, Corresponding author, Accepted

    　View Summary

    Although oral tolerance is a critical system in regulating allergic disorders, the mechanisms by which dietary factors regulate the induction and maintenance of oral tolerance remain unclear. To address this, we explored the differentiation and function of various immune cells in the intestinal immune system under fasting and ad libitum-fed conditions before oral ovalbumin (OVA) administration. Fasting mitigated OVA-specific Treg expansion, which is essential for oral tolerance induction. This abnormality mainly resulted from functional defects in the CX3CR1+ cells responsible for the uptake of luminal OVA and reduction of tolerogenic CD103+ dendritic cells. Eventually, fasting impaired the preventive effect of oral OVA administration on asthma and allergic rhinitis development. Specific food ingredients, namely carbohydrates and arginine, were indispensable for oral tolerance induction by activating glycolysis and mTOR signaling. Overall, prior food intake and nutritional signals are critical for maintaining immune homeostasis by inducing tolerance to ingested food antigens.

  • A purified diet affects intestinal epithelial proliferation and barrier functions through gut microbial alterations

    Shiratori H., Hattori K.M., Nakata K., Okawa T., Komiyama S., Kinashi Y., Kabumoto Y., Kaneko Y., Nagai M., Shindo T., Moritoki N., Kawamura Y.I., Dohi T., Takahashi D., Kimura S., Hase K.

    International Immunology 36 ( 5 ) 223 - 240 2024.05

    ISSN  09538178

    　View Summary

    The gut microbiota plays a crucial role in maintaining epithelial barrier function. Although multiple studies have demonstrated the significance of dietary factors on the gut microbiota and mucosal barrier function, the impact of a purified diet, which has long been used in various animal experiments, on intestinal homeostasis remains to be elucidated. Here, we compared the impact of two different types of diets, a crude diet and an AIN-93G-formula purified diet, on epithelial integrity and the gut microbiota. Purified diet-fed mice exhibited shorter villi and crypt lengths and slower epithelial turnover, particularly in the ileum. In addition, antimicrobial products, including REG3γ, were substantially decreased in purified diet-fed mice. Purified diet feeding also suppressed α1,2-fucosylation on the epithelial surface. Furthermore, the purified diet induced metabolic rewiring to fatty acid oxidation and ketogenesis. 16S ribosomal RNA gene sequencing of the ileal contents and mucus layer revealed distinct gut microbiota compositions between the purified and crude diet-fed mice. Purified diet feeding reduced the abundance of segmented filamentous bacteria (SFB), which potently upregulate REG3γand fucosyltransferase 2 (Fut2) by stimulating group 3 innate lymphoid cells (ILC3s) to produce IL-22. These observations illustrate that the intake of a crude diet secures epithelial barrier function by facilitating SFB colonization, whereas a purified diet insufficiently establishes the epithelial barrier, at least partly owing to the loss of SFB. Our data suggest that the influence of purified diets on the epithelial barrier integrity should be considered in experiments using purified diets.

  • MZB1-mediated IgA secretion suppresses the development and progression of colorectal cancer triggered by gut inflammation.

    Tang Y, Feng X, Cui C, Yu M, Wen Z, Luan Y, Dong L, Hu Z, Zhang R, Liu J, Shinkura R, Hase K, Lu Q, Wang JY.

    Mucosal Immunol. 17 ( 3 ) 450 - 460 2023.12

    Research paper (scientific journal), Accepted,  ISSN  19330219

    　View Summary

    Colorectal cancer (CRC) ranks among the top causes of mortality globally. Gut inflammation is one crucial risk factor that augments CRC development since patients suffering from inflammatory bowel disease have an increased incidence of CRC. The role of immunoglobulin (Ig)A in maintaining gut homeostasis and preventing inflammation has been well established. Our earlier work demonstrated that the marginal zone and B1 cell-specific protein (MZB1) promotes gut IgA secretion and its absence results in pronounced dextran sulfate sodium salt (DSS)-induced colitis. In the present study, we explored the role of MZB1 in CRC development using the azoxymethane (AOM)/DSS-induced CRC model. We observed an increase in both the number and size of the tumor nodules in Mzb1−/− mice compared with Mzb1+/+ mice. The increase in CRC development and progression in Mzb1−/− mice was associated with reduced intestinal IgA levels, altered gut flora, and more severe gut and systemic inflammation. Oral administration of the monoclonal IgA, W27, alleviated both the gut inflammation and AOM/DSS-induced CRC. Notably, cohousing Mzb1+/+ and Mzb1−/− mice from the 10th day after birth led to similar CRC development. Our findings underscore the pivotal role of MZB1-mediated IgA secretion in suppressing the onset and progression of CRC triggered by gut inflammation. Moreover, our study highlights the profound impact of microbiota composition, modulated by gut IgA levels, on gut inflammation. Nonetheless, establishing a direct correlation between the severity of colitis and subsequent CRC development and the presence or absence of a particular microbiota is challenging.

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Papers, etc., Registered in KOARA 【 Display / hide 】

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Reviews, Commentaries, etc. 【 Display / hide 】

  • 腸内細菌による粘膜バリア制御機構

    古平陽太郎, 込山星河, 長谷耕二

    炎症と免疫 32 ( 3 ) 207 - 211 2024.04

    Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media), Joint Work, Last author, Corresponding author

  • マルチオミクスによるIBDにおけるディスバイオーシスの理解

    高橋大輔, 長谷耕二

    実験医学 41 ( 15 ) 204 - 210 2023.09

    Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media), Joint Work, Last author, Corresponding author

  • 腸内細菌と次世代の健康

    鈴木功一郎, 長谷耕二

    Medical Science Digest 49 ( 8 ) 397 - 400 2023.08

    Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media), Joint Work, Last author, Corresponding author

  • 腸内細菌による発達期における免疫インプリンティング

    鈴木功一郎, 長谷耕二

    腸内細菌学雑誌 37 ( 3 ) 149 - 155 2023.07

    Article, review, commentary, editorial, etc. (scientific journal), Joint Work, Last author, Corresponding author

  • 空気中の異物を体内に取り込む呼吸器M細胞の発見

    河合真悟, 木村俊介, 長谷耕二

    呼吸器内科 40 ( 6 ) 590 - 595 2021.12

    Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media), Joint Work

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Presentations 【 Display / hide 】

  • 飢餓ストレスによるリンパ球の動態制御

    HASE Koji

    2017年度生命科学系学会合同年次大会 (ConBio2017), 

    2017.12
    , 

    Oral presentation (invited, special)

  • 腸内細菌由来の酪酸による全身性自己免応答の制御

    HASE Koji

    第22回日本食物繊維学会, 

    2017.11
    , 

    Oral presentation (invited, special)

  • マイクロバイオータとアレルギー

    HASE Koji

    第54回小児アレルギー学会, 

    2017.11
    , 

    Oral presentation (invited, special)

  • Intestinal microbiota-derived metabolites regulate autoimmunity through epigenetic modifications

    HASE Koji

    Fujihara Seminar (Tomakomai, Japan) , 

    2017.09
    , 

    Oral presentation (invited, special)

  • Microbiota-derived metabolites shape host immunity

    HASE Koji

    第59回歯科基礎医学会学術大会, 

    2017.09
    , 

    Oral presentation (invited, special)

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

  • Elucidation of mucosal barrier regulation by intestinal microbiota

    2023.04
    -
    2028.03

    基盤研究(S), Principal investigator

  • Elucidation of Inflammatory disorder induced by intestinal dysbiosis

    2022.06
    -
    2024.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 挑戦的研究（萌芽）, Principal investigator

  • Starvation response of the immune system along the gut-bone marrow axis

    2020.04
    -
    2023.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (A) , Principal investigator

  • 多変量解析による慢性炎症スパイラル形成機構の解明

    2017.07
    -
    2020.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (B), Principal investigator

  • Elucidation of T-independent IgA class switch machinery

    2017.04
    -
    2020.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (B), Principal investigator

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Awards 【 Display / hide 】

  • 第23回日本免疫学会賞

    2020.12

    Type of Award： Award from Japanese society, conference, symposium, etc.

  • 第36回 井上学術賞

    2020.02, 公益財団法人井上科学振興財団, 腸管免疫系の制御機構の解明

    Type of Award： Other

  • 2019年度日本食品免疫学会賞

    2019.10, 日本食品免疫学会, 食品が最初に接する上皮バリアと粘膜免疫系の連携に着目した粘膜バリアシステムの研究

    Type of Award： Award from Japanese society, conference, symposium, etc.

  • 第53回ベルツ賞（2等賞）

    2016.11, べーリンガーインゲルハイム, 宿主-腸内細菌叢相互作用

    Type of Award： Other

  • 第12回日本学術振興会賞

    2016.02, 粘膜面における免疫制御機構の解明

    Type of Award： Other

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Courses Taught 【 Display / hide 】

  • STUDY OF MAJOR FIELD: (BIOCHEMISTRY)

    2024

  • SEMINAR: (BIOCHEMISTRY)

    2024

  • RESEARCH FRONTIERS IN BIOMEDICAL SCIENCE

    2024

  • RESEARCH FOR BACHELOR'S THESIS 1

    2024

  • PHYSICAL CHEMISTRY 1

    2024

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