嶋田　弘子 （シマダ　ヒロコ）

Shimada, Hiroko

写真a

所属（所属キャンパス）

先端研究教育連携スクエア 殿町先端研究教育連携スクエア （三田）

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特任講師（有期）
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経歴 【 表示 ／ 非表示 】

  • 2013年07月
    -
    2016年12月

    アメリカ国立衛生研究所

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  • Stem cell, Neural differentiation

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  • Reserpine maintains photoreceptor survival in retinal ciliopathy by resolving proteostasis imbalance and ciliogenesis defects

    Chen H.Y., Swaroop M., Papal S., Mondal A.K., Song H.B., Campello L., Tawa G.J., Regent F., Shimada H., Nagashima K., de Val N., Jacobson S.G., Zheng W., Swaroop A.

    eLife （eLife）  12 2023年03月

    　概要を見る

    Ciliopathies manifest from sensory abnormalities to syndromic disorders with multi-organ pathologies, with retinal degeneration a highly penetrant phenotype. Photoreceptor cell death is a major cause of incurable blindness in retinal ciliopathies. To identify drug candidates to maintain photoreceptor survival, we performed an unbiased, high-throughput screening of over 6,000 bioactive small molecules using retinal organoids differentiated from induced pluripotent stem cells (iPSC) of rd16 mouse, which is a model of Leber congenital amaurosis (LCA) type 10 caused by mutations in the cilia-centrosomal gene CEP290. We identified five non-toxic positive hits, including the lead molecule reserpine, which maintained photoreceptor development and survival in rd16 organoids. Reserpine also improved photoreceptors in retinal organoids derived from induced pluripotent stem cells of LCA10 patients and in rd16 mouse retina in vivo. Reserpine-treated patient organoids revealed modulation of signaling pathways related to cell survival/death, metabolism, and proteostasis. Further investigation uncovered dysregulation of autophagy associated with compromised primary cilium biogenesis in patient organoids and rd16 mouse retina. Reserpine partially restored the balance between autophagy and the ubiquitin-proteasome system at least in part by increasing the cargo adaptor p62, resulting in improved primary cilium assembly. Our study identifies effective drug candidates in preclinical studies of CEP290 retinal ciliopathies through cross-species drug discovery using iPSC-derived organoids, highlights the impact of proteostasis in the pathogenesis of ciliopathies, and provides new insights for treatments of retinal neurodegeneration.

  • Human PSCs determine the competency of cerebral organoid differentiation via FGF signaling and epigenetic mechanisms

    Ideno H., Imaizumi K., Shimada H., Sanosaka T., Nemoto A., Kohyama J., Okano H.

    iScience （iScience）  25 （ 10 ）  2022年10月

    　概要を見る

    Various culture methods have been developed for maintaining human pluripotent stem cells (PSCs). These PSC maintenance methods exhibit biased differentiation; for example, feeder-dependent PSCs efficiently yield cerebral organoids, but it is difficult to generate organoids from feeder-free PSCs. It remains unknown how PSC maintenance conditions affect differentiation. In this study, we identified fibroblast growth factor (FGF) signaling in feeder-free PSC maintenance as a key factor that determines the differentiation toward cerebral organoids. The inhibition of FGF signaling in feeder-free PSCs rescued organoid generation to the same level in feeder-dependent cultures. FGF inhibition induced DNA methylation at the WNT5A locus, and this epigenetic change suppressed the future activation of non-canonical Wnt signaling after differentiation, leading to reliable cerebral organoid generation. This study underscores the importance of PSC culture conditions for directed differentiation into cerebral organoids, and the epigenetic status regulated by FGF signaling is involved in the underlying mechanisms.

  • In vitro modeling and rescue of ciliopathy associated with IQCB1/NPHP5 mutations using patient-derived cells

    Kruczek K., Qu Z., Welby E., Shimada H., Hiriyanna S., English M.A., Zein W.M., Brooks B.P., Swaroop A.

    Stem Cell Reports （Stem Cell Reports）  17 （ 10 ） 2172 - 2186 2022年10月

    ISSN  22136711

    　概要を見る

    Mutations in the IQ calmodulin-binding motif containing B1 (IQCB1)/NPHP5 gene encoding the ciliary protein nephrocystin 5 cause early-onset blinding disease Leber congenital amaurosis (LCA), together with kidney dysfunction in Senior-Løken syndrome. For in vitro disease modeling, we obtained dermal fibroblasts from patients with NPHP5-LCA that were reprogrammed into induced pluripotent stem cells (iPSCs) and differentiated into retinal pigment epithelium (RPE) and retinal organoids. Patient fibroblasts and RPE demonstrated aberrantly elongated ciliary axonemes. Organoids revealed impaired development of outer segment structures, which are modified primary cilia, and mislocalization of visual pigments to photoreceptor cell soma. All patient-derived cells showed reduced levels of CEP290 protein, a critical cilia transition zone component interacting with NPHP5, providing a plausible mechanism for aberrant ciliary gating and cargo transport. Disease phenotype in NPHP5-LCA retinal organoids could be rescued by adeno-associated virus (AAV)-mediated IQCB1/NPHP5 gene augmentation therapy. Our studies thus establish a human disease model and a path for treatment of NPHP5-LCA.

  • A next-generation iPSC-derived forebrain organoid model of tauopathy with tau fibrils by AAV-mediated gene transfer

    Shimada H., Sato Y., Sasaki T., Shimozawa A., Imaizumi K., Shindo T., Miyao S., Kiyama K., Kondo T., Shibata S., Ishii S., Kuromitsu J., Aoyagi H., Ito D., Okano H.

    Cell Reports Methods （Cell Reports Methods）  2 （ 9 ）  2022年09月

    　概要を見る

    It is known that the human cellular models of Alzheimer's disease (AD) and tauopathy can only recapitulate the very early stage of the disease. To overcome these limitations, we developed a technology to make forebrain organoids (FBOs) from feeder-free induced pluripotent stem cells (iPSC)s by regulating a FGF2 concentration and applied this method to generate FBOs from patients with familial AD (fAD FBOs). The obtained fAD FBOs recapitulated the amyloid-β pathology and increased tau phosphorylation but not tau aggregates. To fully induce the tau pathology, FBOs were injected with adeno-associated virus (AAV)-expressing P301L mutant tau. In these Tau-P301L FBOs, tau fibrils were observed in the neuronal cell body and neurites with immunoelectron microscopy, in addition to the sarkosyl-insoluble and thioflavin S-positive phospho-tau aggregates. Collectively, this model can be used as a platform for investigating pathogenetic mechanisms and evaluation of target molecules for drug discovery for tauopathy.

  • In Vitro Modeling Using Ciliopathy-Patient-Derived Cells Reveals Distinct Cilia Dysfunctions Caused by CEP290 Mutations

    嶋田 弘子

    CELL REPORTS 20 （ 2 ） 384 - 396 2017年07月

    研究論文（学術雑誌）,  ISSN  2211-1247

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研究発表 【 表示 ／ 非表示 】

  • Development of induced pluripotent stem cells (iPSCs)-based therapies for blinding retinal neurodegenerative diseases.

    嶋田 弘子

    2014 Focus on Fellows, NEI/NIH, 

    2014年10月
    , 

    ポスター発表

  • Development of induced pluripotent stem cells (iPSCs)-based therapies for blinding retinal neurodegenerative diseases.

    嶋田 弘子

    NIH-Japan-JSPS Symposium, 

    2014年10月
    , 

    ポスター発表

  • Efficient derivation of neural stem cells from common marmoset ES　cells and iPS cells

    嶋田 弘子

    ISSCR 10th Annual Meeting, 

    2012年06月
    , 

    ポスター発表

  • Efficient derivation of neural stem cells from common marmoset ES　cells and iPS cells.

    嶋田 弘子

    Frontiers in Biomedical Researches on Marmosets as a Primate Model Japan Society for Marmoset Research, 

    2012年02月
    , 

    ポスター発表

  • Efficient derivation of neural stem cells from common marmoset ES cells and iPS cells

    嶋田 弘子

    Neuroscience 2011, SfN's 41st annual meeting, 

    2011年11月
    , 

    ポスター発表

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受賞 【 表示 ／ 非表示 】

  • International Society for Stem Cell Research (ISSCR), Travel award

    2011年06月

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担当授業科目 【 表示 ／ 非表示 】

  • 生理学Ⅱ

    2024年度

  • 生理学Ⅱ

    2023年度

  • 生理学Ⅱ

    2022年度

  • 生理学Ⅱ

    2021年度

  • 生理学Ⅱ

    2020年度

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