Shimmura, Shigeto

写真a

Affiliation

School of Medicine, Department of Ophthalmology （Shinanomachi）

Position

Associate Professor

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Academic Background 【 Display / hide 】

  • 1989.03

    Keio University, 医学部

    Graduated

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Research Areas 【 Display / hide 】

  • Ophthalmology

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Papers 【 Display / hide 】

  • Transplantation of iPSC-derived corneal endothelial substitutes in a monkey corneal edema model

    Hatou S., Sayano T., Higa K., Inagaki E., Okano Y., Sato Y., Okano H., Tsubota K., Shimmura S.

    Stem Cell Research （Stem Cell Research)  55 2021.08

    ISSN  18735061

    　View Summary

    Objective: In order to provide regenerative therapy for millions of patients suffering from corneal blindness globally, we derived corneal endothelial cell substitute (CECSi) cells from induced pluripotent stem cells (iPSCs) to treat corneal edema due to endothelial dysfunction (bullous keratopathy). Methods and results: We developed an efficient xeno-free protocol to produce CECSi cells from both research grade (Ff-MH09s01 and Ff-I01s04) and clinical grade (QHJI01s04) iPSCs. CECSi cells formed a hexagonal confluent monolayer with Na, K-ATPase alpha 1 subunit expression (ATP1A1), tight junctions, N-cadherin adherence junction formation, and nuclear PITX2 expression, which are all characteristics of corneal endothelial cells. CECSi cells can be cryopreserved, and thawed CECSi cell suspensions also expressed N-cadherin and ATP1A1. Residual undifferentiated iPSCs in QHJI01s04-derived CECSi cells was below 0.01%. Frozen stocks of Ff-I01s04- and QHJI01s04-derived CECSi cells were transported, thawed and transplanted into a monkey corneal edema model. CECSi-transplanted eyes significantly reduced corneal edema compared to control group. Conclusion: Our results show a promising approach to provide bullous keratopathy patients with an iPS-cell-based cell therapy to recover useful vision.

  • Observation of chronic graft-versus-host disease mouse model cornea with in vivo confocal microscopy

    Shimizu S., Sato S., Taniguchi H., Shimizu E., He J., Hayashi S., Negishi K., Ogawa Y., Shimmura S.

    Diagnostics （Diagnostics)  11 （ 8 ）  2021.08

    　View Summary

    Graft-versus-host disease (GVHD) is a major complication after hematopoietic stem cell transplantation (HSCT), and ocular GVHD can cause severe dry eye disease that can lead to visual impairment. Epithelial damage, vascular invasion, corneal fibrosis, and corneal perforation may occur in severe cases. It is generally accepted that inflammatory cells such as dendritic cells and T cells contribute to this pathological condition. However, it is still unknown what pathological condition occurs on the ocular surface after HSCT, and when. We therefore observed the dynamics of inflammatory cells in the cornea of chronic GVHD (cGVHD) model mice from 1 to 4 weeks after bone marrow transplantation (BMT) by in vivo confocal microscopy (IVCM) and considered the relationship with the pathophysiology of ocular GVHD (tear volume, corneal epithelial damage). In the allogeneic group, neovascularization occurred in all eyes at 1 week after BMT, although almost all vessels disappeared at 2 weeks after BMT. In addition, we revealed that infiltration of globular cells, and tortuosity and branching of nerves in the cornea occurred in both cGVHD mice and human cGVHD patients. Thus, we consider that cGVHD mouse model study by IVCM reproduces the state of ocular GVHD and may contribute to elucidating the pathological mechanism for ocular GVHD.

  • Targeted expression of tgfbip peptides in mouse and human tissue by maldi-mass spectrometry imaging

    Anandalakshmi V., Hochart G., Bonnel D., Stauber J., Shimmura S., Lakshminarayanan R., Pervushin K., Mehta J.S.

    Separations （Separations)  8 （ 7 ）  2021.07

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    Stromal corneal dystrophies are a group of hereditary disorders caused by mutations in the TGFBI gene. The mutant TGFBIp is prone to protein aggregation and the mutant protein gets deposited in the cornea, leading to severe visual impairment. The mutations lead to a corneal specific protein aggregation suggesting the involvement of tissue-specific factors. The exact molecular mechanism of the process of tissue-specific protein aggregation remains to be elucidated. Differential proteolysis of mutant TGFBIp is a critical component of the disease pathology. The differential prote-olysis gives rise to shorter peptides that are highly aggregation-prone and initiate the aggregation cascade. Analyzing the proteolytic processing of the different TGFBIp mutant may provide insight to aid in understanding the amyloid aggregation mechanism. We developed a MALDI-MSI methodology to identify expression and spatial localization of TGFBIp peptides in the cornea. Corneal tissue samples were collected from both control and dystrophic patients (with 2 different mutations), embedded in OCT and sectioned. The sections were trypsin digested and subjected to mass spec-trometry imaging using a targeted approach to detect TGFBIp. MALDI-MSI identified peptides from TGFBIp that co-localized with the amyloid corneal deposits. In addition to the relative abundance data, the specific location of the peptides across the corneal sections as molecular signatures was also identified. Spatial distribution and intensity of the TGFBIp peptides showed differences between diseased and control models but also between the two LCD phenotypes. The TGFBIp peptide with m/z of 787.474 and m/z of 1179.579 showed increased expression in both LCD mutants compared to the controls. The peptide with m/z of 929.5 showed increased expression in the LCD phenotype with H626R mutation while the peptide with m/z of 1315.802 was abundant in the sample with R124C mutation. This initial report of 2D spatial protein signature and localization of TGFBIp may be expanded to other mutations to understand the proteolytic patterns of TGFBIp in different mutations.

  • Mscs become collagen-type i producing cells with different phenotype in allogeneic and syngeneic bone marrow transplantation

    Rusch R.M., Ogawa Y., Sato S., Morikawa S., Inagaki E., Shimizu E., Tsubota K., Shimmura S.

    International Journal of Molecular Sciences （International Journal of Molecular Sciences)  22 （ 9 ）  2021.05

    ISSN  16616596

    　View Summary

    Mesenchymal stem cells (MSCs) have been widely used in therapeutic applications for many decades. However, more and more evidence suggests that factors such as the site of origin and pre-implantation treatment have a crucial impact on the result. This study investigates the role of freshly isolated MSCs in the lacrimal gland after allogeneic transplantation. For this purpose, MSCs from transgenic GFP mice were isolated and transplanted into allogeneic and syngeneic recipients. While the syngeneic MSCs maintained a spherical shape, allogeneic MSCs engrafted into the tissue as spindle-shaped cells in the interstitial stroma. Furthermore, the MSCs produced collagen type I in more than 85% to 95% of the detected GFP+ MSCs in the recipients of both models, supposedly contributing to pathogenic fibrosis in allogeneic recipients compared to syngeneic models. These findings indicate that allogeneic MSCs act completely differently from syngeneic MSCs, highlighting the importance of understanding the exact mechanisms behind MSCs.

  • Human corneal limbal organoids maintaining limbal stem cell niche function

    Higa K., Higuchi J., Kimoto R., Miyashita H., Shimazaki J., Tsubota K., Shimmura S.

    Stem Cell Research （Stem Cell Research)  49 2020.12

    ISSN  18735061

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    Corneal epithelial stem cells reside in the limbal area between the cornea and conjunctiva. We examined the potential use of limbal organoids as a source of transplantable limbal stem cells. After treating tissue with collagenase, limbal cells were seeded onto Matrigel and cultivated using limbal phenotype maintenance medium. After 1-month, approximately 500 organoids were formed from one donor cornea. Organoids derived from vertical sites (superior and inferior limbus) showed large colony forming efficiency, a higher ratio of slow cycling cells and N-cadherin-expressing epithelial cells compared to horizontal sites. The progenitor markers Keratin (K) 15 and p63 were expressed in epithelial sheets engineered form a single organoid. Organoids transplanted in the limbus of a rabbit limbal deficiency model confirmed the presence of organoid-derived cells extending on to host corneas by immunohistochemistry. Our data show that limbal organoids with a limbal phenotype can be maintained for up to 1 month in vitro which can each give rise to a fully stratified corneal epithelium complete with basal progenitor cells. Limbal organoids were successfully engrafted in vivo to provide epithelial cells in a rabbit limbal deficiency model, suggesting that organoids may be an efficient cell source for clinical use.

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

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Reviews, Commentaries, etc. 【 Display / hide 】

  • Reply

    Deng S.X., Borderie V., Chan C.C., Dana R., Figueiredo F.C., Gomes J.A.P., Pellegrini G., Shimmura S., Kruse F.E.

    Cornea (Cornea)  38 ( 12 ) E56 - E57 2019.12

    ISSN  02773740

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

  • iPS細胞由来角膜内皮代替細胞移植のFirst-in-human臨床研究

    2021.04
    -
    2024.03

    国立研究開発法人日本医療研究開発機構, 日本医療研究開発機構研究費, Principal Investigator

  • ドラッグ・リポジショニングによるフックス角膜変性症治療薬の開発

    2019.04
    -
    2022.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 榛村　重人, Grant-in-Aid for Scientific Research (C), Principal Investigator

  • フックス角膜内皮変性症の疾患特異的iPS細胞による病態解明

    2016.04
    -
    2019.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 榛村　重人, Grant-in-Aid for Scientific Research (C), Principal Investigator

  • iPS細胞由来治療用角膜内皮代替細胞に関する臨床研究

    2016.04
    -
    2019.03

    Principal Investigator

  • 皮膚由来多能性前駆細胞から角膜内皮細胞への分化誘導

    2013.04
    -
    2016.03

    Principal Investigator

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Awards 【 Display / hide 】

  • American Academy of Ophthalmology Achievement Award

    2010.05

  • 日本角膜学会学術奨励賞

    2004.02

  • 東京歯科大学学長奨励研究賞

    2003.07

  • 三四会奨励賞

    2000.11

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Courses Taught 【 Display / hide 】

  • LECTURE SERIES, OPHTHALMOLOGY

    2021

  • LECTURE SERIES, OPHTHALMOLOGY

    2020

  • ADVANCED MEDICAL TECHNOLOGIES

    2020

  • LECTURE SERIES, OPHTHALMOLOGY

    2019

  • CLINICAL CLERKSHIP IN OPHTHALMOLOGY

    2019

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Courses Previously Taught 【 Display / hide 】

  • 眼科学

    Keio University, 2015, Full academic year, Major subject, Within own ｆaculty

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Social Activities 【 Display / hide 】

  • Asian Cornea Society

    2009
    -
    Present

  • 日本炎症・再生医療学会

    2004
    -
    Present

  • 日本再生医療学会

    2003
    -
    Present

  • American Academy of Ophthalmology

    2002
    -
    Present

  • 日本角膜学会

    1998
    -
    Present

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