Details of a Researcher - Kase, Yoshitaka

Spinal cord injury regenerative therapy development: integration of design of experiments.

Okano Y, Okano H, Kase Y.

Neural Regeneration Research 2024.07

Research paper (scientific journal), Corresponding author, Accepted
Chronological transitions of hepatocyte growth factor treatment effects in spinal cord injury tissue

Inflammation and Regeneration 2024.03

Research paper (scientific journal), Joint Work, Accepted
Hepatocyte growth factor pretreatment boosts functional recovery after spinal cord injury through human iPSC-derived neural stem/progenitor cell transplantation.

Suematsu Y, Nagoshi N, Shinozaki M, Kase Y, Saijo Y, Hashimoto S, Shibata T, Kajikawa K, Kamata Y, Ozaki M, Yasutake K, Shindo T, Shibata S, Matsumoto M, Nakamura M, Okano H

Inflammation and regeneration (Inflammation and Regeneration) 43 ( 1 ) 50 - 50 2023.10

ISSN 1880-9693

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BACKGROUND: Human induced pluripotent stem cell-derived neural stem/progenitor cell (hiPSC-NS/PC)-based cell transplantation has emerged as a groundbreaking method for replacing damaged neural cells and stimulating functional recovery, but its efficacy is strongly influenced by the state of the injured spinal microenvironment. This study evaluates the impact of a dual therapeutic intervention utilizing hepatocyte growth factor (HGF) and hiPSC-NS/PC transplantation on motor function restoration following spinal cord injury (SCI). METHODS: Severe contusive SCI was induced in immunocompromised rats, followed by continuous administration of recombinant human HGF protein into the subarachnoid space immediately after SCI for two weeks. Acute-phase histological and RNA sequencing analyses were conducted. Nine days after the injury, hiPSC-NS/PCs were transplanted into the lesion epicenter of the injured spinal cord, and the functional and histological outcomes were determined. RESULTS: The acute-phase HGF-treated group exhibited vascularization, diverse anti-inflammatory effects, and activation of endogenous neural stem cells after SCI, which collectively contributed to tissue preservation. Following cell transplantation into a favorable environment, the transplanted NS/PCs survived well, facilitating remyelination and neuronal regeneration in host tissues. These comprehensive effects led to substantial enhancements in motor function in the dual-therapy group compared to the single-treatment groups. CONCLUSIONS: We demonstrate that the combined therapeutic approach of HGF preconditioning and hiPSC-NS/PC transplantation enhances locomotor functional recovery post-SCI, highlighting a highly promising therapeutic strategy for acute to subacute SCI.
- Access to Document (DOI)
Neuroprotective effects of genome-edited human iPS cell-derived neural stem/progenitor cells on traumatic brain injury

Imai, R., Tamura, R., Yo, M., Sato, M., Fukumura, M., Takahara, K., Kase, Y., Okano, H., & Toda, M.

Stem Cells (Stem Cells) 41 ( 6 ) 603 - 616 2023.04

Research paper (scientific journal), Accepted, ISSN 10665099

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Despite developing neurosurgical procedures, few treatment options have achieved functional recovery from traumatic brain injury (TBI). Neural stem/progenitor cells (NS/PCs) may produce a long-term effect on neurological recovery. Although induced pluripotent stem cells (iPSCs) can overcome ethical and practical issues of human embryonic or fetal-derived tissues in clinical applications, the tumorigenicity of iPSC-derived populations remains an obstacle to their safe use in regenerative medicine. We herein established a novel treatment strategy for TBI using iPSCs expressing the enzyme-prodrug gene yeast cytosine deaminase-uracil phosphoribosyl transferase (yCD-UPRT). NS/PCs derived from human iPSCs displayed stable and high transgene expression of yCD-UPRT following CRISPR/Cas9-mediated genome editing. In vivo bioluminescent imaging and histopathological analysis demonstrated that NS/PCs concentrated around the damaged cortex of the TBI mouse model. During the subacute phase, performances in both beam walking test and accelerating rotarod test were significantly improved in the treatment group transplanted with genome-edited iPSC-derived NS/PCs compared with the control group. The injury area visualized by extravasation of Evans blue was smaller in the treatment group compared with the control group, suggesting the prevention of secondary brain injury. During the chronic phase, cerebral atrophy and ventricle enlargement were significantly less evident in the treatment group. Furthermore, after 5-fluorocytosine (5-FC) administration, 5-fluorouracil converted from 5-FC selectively eliminated undifferentiated NS/PCs while preserving the adjacent neuronal structures. NS/PCs expressing yCD-UPRT can be applied for safe regenerative medicine without the concern for tumorigenesis.
- Access to Document (DOI)
The original strain of SARS-CoV-2, the Delta variant, and the Omicron variant infect microglia efficiently, in contrast to their inability to infect neurons: Analysis using 2D and 3D cultures

Kase Y, Sonn I, Goto M, Murakami R, Sato T, Okano H

Experimental Neurology (Experimental Neurology) 363 114379 - 114379 2023.03

Research paper (scientific journal), Lead author, ISSN 00144886

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COVID-19 causes neurological damage, systemic inflammation, and immune cell abnormalities. COVID-19-induced neurological impairment may be caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which directly infects cells of the central nervous system (CNS) and exerts toxic effects. Furthermore, SARS-CoV-2 mutations occur constantly, and it is not well understood how the infectivity of the virus to cells of the CNS changes as the virus mutates. Few studies have examined whether the infectivity of cells of CNS - neural stem/progenitor cells (NS/PCs), neurons, astrocytes, and microglia - varies among SARS-CoV-2 mutant strains. In this study, therefore, we investigated whether SARS-CoV-2 mutations increase infectivity to CNS cells, including microglia. Since it was essential to demonstrate the infectivity of the virus to CNS cells in vitro using human cells, we generated cortical neurons, astrocytes, and microglia from human induced pluripotent stem cells (hiPSCs). We added pseudotyped lentiviruses of SARS-CoV-2 to each type of cells, and then we examined their infectivity. We prepared three pseudotyped lentiviruses expressing the S protein of the original strain (the first SARS-CoV-2 discovered in the world), the Delta variant, and the Omicron variant on their envelopes and analyzed differences of their ability to infect CNS cells. We also generated brain organoids and investigated the infectivity of each virus. The viruses did not infect cortical neurons, astrocytes, or NS/PCs, but microglia were infected by the original, Delta, and Omicron pseudotyped viruses. In addition, DPP4 and CD147, potential core receptors of SARS-CoV-2, were highly expressed in the infected microglia, while DPP4 expression was deficient in cortical neurons, astrocytes, and NS/PCs. Our results suggest that DPP4, which is also a receptor for Middle East respiratory syndrome-coronavirus (MERS-CoV), may play an essential role in the CNS. Our study is applicable to the validation of the infectivity of viruses that cause various infectious diseases in CNS cells, which are difficult to sample from humans.
- Access to Document (DOI)

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Reviews, Commentaries, etc. 【 Display / hide 】

【神経の再生-臨床に届く基礎研究】外傷性脳損傷の再生治療の現状と軸索再生メカニズム

加瀬義高

細胞 ((株)ニュー・サイエンス社) 55 ( 10 ) 766 - 769 2023.09

ISSN 1346-7557

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外傷性脳損傷により欠損した脳組織は,そのままでは完全に自然回復することはなく,麻痺や高次脳機能障害などが残存してしまう。現在まで,そのように失った脳機能を回復するような再生医療の実現には至っていない。ここでは,外傷性脳損傷の基礎研究の現状と,損傷に対する再生医療の実現をはばむ障壁・問題について概説し,筆者らが発見した神経軸索を伸長する化合物の紹介と,今後の展望について論じる。(著者抄録)
SAH/Spasmの基礎研究　くも膜下出血による炎症反応は局所にとどまらず大脳皮質全体に及んで神経細胞死を引き起こす

山田浩貴, 加瀬義高, 高橋里史, 戸田正博

くも膜下出血と脳血管攣縮 (SAH) 38 66 - 66 2023.07

ISSN 2759-2405
COVID-19関連中枢神経障害に対する治療薬の開発研究

加瀬義高

先進医薬研究振興財団研究成果報告集 ((公財)先進医薬研究振興財団) 2022年度 58 - 63 2023.03

ISSN 2189-1303
ヒトのニューロンにおける神経突起伸長メカニズムの解析

神経化学 Vol. 61 (No. 2), 2022, 96–100 2022.12

Article, review, commentary, editorial, etc. (scientific journal), Single Work, Lead author
成体神経新生におけるp38 MAPKシグナルの役割

Clinical Neuroscience (中外医学社) 40 ( 9 ) 2022.09

Article, review, commentary, editorial, etc. (scientific journal), Lead author

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Presentations 【 Display / hide 】

神経再生医学の最前線ー細胞移動・軸索伸展から機能回復までー神経突起伸展の分子機構と脊髄損傷および外傷性脳損傷の再生医療への応用

第22回　日本再生医療学会総会 (京都) ,

2023.03
,
Symposium, workshop panel (nominated)
The GADD45G/p38 MAPK/CDC25B signaling pathway enhances neurite outgrowth by promoting microtubule polymerization

第43回日本炎症・再生医学会,

2022.07
,
Oral presentation (general)
ウイルス毒性増悪因子としてのCCN family member 1 の COVID-19 関連神経障害への関与

加瀬義高

第12回日本CCNファミリー研究会,

2021.09
,
Symposium, workshop panel (nominated)
EXPRESSION OF ACE2 AND A VIRAL VIRULENCE-REGULATING FACTOR CCN FAMILY MEMBER 1 IN HUMAN IPSC-DERIVED NEURAL CELLS: IMPLICATIONS FOR COVID-19-RELATED CNS DISORDERS

ISSCR 2021 Annual Meeting, to be held virtually from 21 June - 26 June, 2021.,

2021.07
Expression of ACE2 and a viral virulence-regulating factor CCN family member 1: implications for COVID-19-related CNS disorders

第42回日本炎症・再生医学会,

2021.07
,
Oral presentation (general)

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

神経幹細胞移植と神経突起伸長促進化合物を組み合わせた外傷性脳損傷の再生治療研究

2022.04

-

2024.03

Grants-in-Aid for Scientific Research, Grant-in-Aid for Early-Career Scientists, No Setting
障害海馬での神経幹細胞の枯渇を招かない長期的な神経再生の基礎的研究

2019.04

-

2022.03

Keio University, Grant-in-Aid for Early-Career Scientists, Other, Principal investigator

　View Summary

近年報告されている脳内栄養因子等を用いた脳梗塞又はアルツハイマー病モデルマウス治療に関する研究においては、一時的な神経新生は認められるが、それらを用いることにより存神経幹細胞の枯渇を招く恐れがあり、治療後長期にわたってどのような弊害が出てくるのかわかっていない。本研究では、脳梗塞モデルマウス、認知症モデルマウスにおける障害海馬において残存神経幹細胞の枯渇を招かずに中長期的に神経回復を試みている。

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Intellectual Property Rights, etc. 【 Display / hide 】

Kits for promoting neurite outgrowth and use thereof

Date applied： 2021-089367

Patent, Single
NEUROSPHERE FOR SPINAL CORD INJURY TREATMENT AND USE THEREOF

Date applied： 2019-215161

Date published： 2021-084882

Patent, Single

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Awards 【 Display / hide 】

藤田医科大学総合医科学研究部門　優秀賞

2024.12

Type of Award： Other
ふじた産学連携特別賞

2023.10

Type of Award： Award from Japanese society, conference, symposium, etc.
藤田医科大学医学会優秀演題賞

2023.10

Type of Award： Award from Japanese society, conference, symposium, etc.
The Award for Young Investigator of Japanese Society for Neurochemistry

2022.07, The Japanese Society of Neurochemistry

Type of Award： International academic award (Japan or overseas)
優秀発表賞

2021.10, 第64回日本神経化学会大会, ヒトのニューロンにおける神経突起伸長メカニズムの解明と神経突起伸長化合物の探索

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

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Courses Previously Taught 【 Display / hide 】

老年医学 (生活習慣病）

東京都立大学

2020.04

-

2022.03
,
Undergraduate (specialized), Lecture, Outside own faculty (within Keio)
老年医学　高齢者の臨床（認知症とその対応）

東京都立大学

2018.04

-

2019.03
,
Spring Semester, Lecture, Outside own faculty (within Keio)
PBLチュートリアル教育

東京大学

2018.04

-

2019.03
,
Undergraduate (specialized), Seminar, Outside own faculty (within Keio)