研究者詳細 - 森本　悟

森本　悟（モリモト　サトル）

Morimoto, Satoru

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）

職名: 特任准教授（有期）

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Maiden voyage: induced pluripotent stem cell-based drug screening for amyotrophic lateral sclerosis

Ito D., Morimoto S., Takahashi S., Okada K., Nakahara J., Okano H.

Brain : a journal of neurology （Brain : a journal of neurology） 146 （ 1 ） 13 - 19 2023年01月

　概要を見る

Using patient-derived induced pluripotent stem cells, neurodegenerative disease phenotypes have been recapitulated and their pathogenesis analysed leading to significant progress in drug screening. In amyotrophic lateral sclerosis, high-throughput screening using induced pluripotent stem cells-derived motor neurons has identified candidate drugs. Owing to induced pluripotent stem cell-based drug evaluation/screening, three compounds, retigabine, ropinirole and bosutinib, have progressed to clinical trials. Retigabine blocks hyperexcitability and improves survival in amyotrophic lateral sclerosis patient-derived motor neurons. In a randomized clinical trial (n = 65), treatment with retigabine reduced neuronal excitability after 8 weeks. Ropinirole, identified in a high-throughput screening, attenuates pathological phenotypes in patient-derived motor neurons. In a trial limited by a small sample size (n = 20), ropinirole was tolerable and had clinical benefits on function and survival. A phase 1 study of bosutinib has reported safety and tolerability for 12 weeks. Thus, these clinical trials show safety and positive effects and confirm the reliability of stem cell-based drug discovery. This novel strategy leads to reduced costs and time when compared to animal testing and opens new avenues for therapy in intractable diseases.
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Intranasal Sendai virus-based SARS-CoV-2 vaccine using a mouse model

Morimoto S., Saeki K., Takeshita M., Hirano K., Shirakawa M., Yamada Y., Nakamura S., Ozawa F., Okano H.

Genes to Cells （Genes to Cells） 28 （ 1 ） 29 - 41 2023年01月

ISSN 13569597

　概要を見る

The coronavirus disease 2019 (COVID-19) epidemic remains worldwide. The usefulness of the intranasal vaccine and boost immunization against severe acute respiratory syndrome-related coronavirus (SARS-CoV-2) has recently received much attention. We developed an intranasal SARS-CoV-2 vaccine by loading the receptor binding domain of the S protein (S-RBD) of SARS-CoV-2 as an antigen into an F-deficient Sendai virus vector. After the S-RBD-Fd antigen with trimer formation ability was intranasally administered to mice, S-RBD-specific IgM, IgG, IgA, and neutralizing antibody titers were increased in serum or bronchoalveolar lavage fluid for 12 weeks. Furthermore, in mice that received a booster dose at week 8, a marked increase in neutralizing antibodies in the serum and bronchoalveolar lavage fluid was observed at the final evaluation at week 12, which neutralized the pseudotyped lentivirus expressing the SARS-CoV-2 spike protein, indicating the usefulness of the Sendai virus-based SARS-CoV-2 intranasal vaccine.
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Single transcription factor efficiently leads human induced pluripotent stem cells to functional microglia

Sonn I., Honda-Ozaki F., Yoshimatsu S., Morimoto S., Watanabe H., Okano H.

Inflammation and Regeneration （Inflammation and Regeneration） 42 （ 1 ） 2022年12月

　概要を見る

Background: Microglia are innate immune cells that are the only residential macrophages in the central nervous system. They play vital physiological roles in the adult brain and during development. Microglia are particularly in the spotlight because many genetic risk factors recently identified for neurodegenerative diseases are largely expressed in microglia. Rare polymorphisms in these risk alleles lead to abnormal activity of microglia under traumatic or disease conditions. Methods: In the present study, to investigate the multifaceted functions of human microglia, we established a novel robust protocol to generate microglia from human induced pluripotent stem cells (hiPSCs) using a combination of cytokines and small chemicals essential for microglia ontogeny. Moreover, we highly enhanced the microglial differentiation efficiency by forcing the expression of PU.1, a crucial transcription factor for microglial development, during posterior mesoderm differentiation. Results: By our novel method, we demonstrated the generation of a greater number of hiPSC-derived microglia (hiMGLs, approximately 120-folds) than the prior methods (at most 40-folds). Over 90% of the hiMGLs expressed microglia-specific markers, such as CX3CR1 and IBA-1. Whole-transcriptome analysis revealed that these hiMGLs are similar to human primary microglia but differ from monocytes/macrophages. Furthermore, the specific physiological functions of microglia were confirmed through indices of lipopolysaccharide responsiveness, phagocytotic ability, and inflammasome formation. By co-culturing these hiMGLs with mouse primary neurons, we demonstrated that hiMGLs can regulate the activity and maturation of neurons. Conclusions: In this study, our new simple, rapid, and highly efficient method for generating microglia from hiPSCs will prove useful for future investigations on microglia in both physiological and disease conditions, as well as for drug discovery.
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Multimodal analyses of a non-human primate model harboring mutant amyloid precursor protein transgenes driven by the human EF1α promoter.

Yoshimatsu S., Seki F., Okahara J., Watanabe H., Sasaguri H., Haga Y., Hata J.i., Sanosaka T., Inoue T., Mineshige T., Lee C.Y., Shinohara H., Kurotaki Y., Komaki Y., Kishi N., Murayama A.Y., Nagai Y., Minamimoto T., Yamamoto M., Nakajima M., Zhou Z., Nemoto A., Sato T., Ikeuchi T., Sahara N., Morimoto S., Shiozawa S., Saido T.C., Sasaki E., Okano H.

Neuroscience Research （Neuroscience Research） 185 49 - 61 2022年12月

ISSN 01680102

　概要を見る

Alzheimer's disease (AD) is the leading cause of dementia which afflicts tens of millions of people worldwide. Despite many scientific progresses to dissect the AD's molecular basis from studies on various mouse models, it has been suffered from evolutionary species differences. Here, we report generation of a non-human primate (NHP), common marmoset model ubiquitously expressing Amyloid-beta precursor protein (APP) transgenes with the Swedish (KM670/671NL) and Indiana (V717F) mutations. The transgene integration of generated two transgenic marmosets (TG1&TG2) was thoroughly investigated by genomic PCR, whole-genome sequencing, and fluorescence in situ hybridization. By reprogramming, we confirmed the validity of transgene expression in induced neurons in vitro. Moreover, we discovered structural changes in specific brain regions of transgenic marmosets by magnetic resonance imaging analysis, including in the entorhinal cortex and hippocampus. In immunohistochemistry, we detected increased Aβ plaque-like structures in TG1 brain at 7 years old, although evident neuronal loss or glial inflammation was not observed. Thus, this study summarizes our attempt to establish an NHP AD model. Although the transgenesis approach alone seemed not sufficient to fully recapitulate AD in NHPs, it may be beneficial for drug development and further disease modeling by combination with other genetically engineered models and disease-inducing approaches.
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Diverse limbic comorbidities cause limbic and temporal atrophy in lewy body disease

Sakurai K., Kaneda D., Morimoto S., Uchida Y., Inui S., Kimura Y., Cai C., Kato T., Ito K., Hashizume Y.

Parkinsonism and Related Disorders （Parkinsonism and Related Disorders） 105 52 - 57 2022年12月

ISSN 13538020

　概要を見る

Background: In contrast to Alzheimer's disease (AD)-related pathology, the influence of comorbid limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) or argyrophilic grains (AG) on structural imaging in Lewy body disease (LBD) has seldom been evaluated. Objective: This study aimed to investigate whether non-AD limbic comorbidities, including LATE-NC and AG, cause cortical atrophy in LBD. Methods: Seventeen patients with pathologically confirmed LBD with lower Braak neurofibrillary tangle stage (<IV) and 10 healthy controls (HC) were included. Based on the presence of comorbid LATE-NC or AG, LBD patients were subdivided into nine patients with these proteinopathies (mixed LBD [mLBD]) and eight without (pure LBD [pLBD]). In addition to clinical feature evaluation, gray matter atrophy on voxel-based morphometry was compared between the two LBD and HC groups. Results: The mean age at antemortem magnetic resonance imaging of the mLBD patients was higher than that of the pLBD patients (84.3 ± 3.9 vs. 76.5 ± 10.5; p = .046). Irrespective of the presence or absence of comorbid LATE-NC or AG, all patients were clinically diagnosed with probable dementia with Lewy bodies or Parkinson's disease with dementia, respectively. Compared to the pLBD group, the mLBD group showed more conspicuous cortical atrophy of the bilateral hippocampus, amygdala, and temporal pole. Conclusions: Non-AD limbic comorbidities, including LATE-NC and AG, are associated with limbic and temporal atrophy in older patients with LBD. Therefore, the possibility of non-AD limbic comorbidities should be considered in the diagnosis of elderly patients with dementia with clinical symptoms of LBD and medial temporal atrophy.
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