研究者詳細 - 成瀬　恵治

論文 - 成瀬　恵治

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TRPV2 mediates stress resilience in mouse cardiomyocytes 査読

Dong Y, Wang G, Ujihara Y, Chen Y, Yoshida M, Nakamura K, Katanosaka K, Naruse K, Katanosaka Y

Communications Biology 8 ( 1 ) 2025年5月

Stress-experienced monocytes/macrophages lose anti-inflammatory function via β2-adrenergic receptor in skin allergic inflammation 査読

Hitoshi Urakami, Soichiro Yoshikawa, Kei Nagao, Kensuke Miyake, Yuki Fujita, Ayaka Komura, Miho Nakashima, Ryusuke Umene, Shuhei Sano, Zheyu Hu, Emi Nishii, Atsushi Fujimura, Takeshi Y. Hiyama, Keiji Naruse, Hajime Karasuyama, Tsuyoshi Inoue, Mitsutoshi Tominaga, Kenji Takamori, Shin Morizane, Sachiko Miyake

Journal of Allergy and Clinical Immunology 155 ( 3 ) 865 - 879 2025年3月

Mechanical signaling through membrane tension induces somal translocation during neuronal migration 査読

Minegishi T., Hasebe H., Aoyama T., Naruse K., Takahashi Y., Inagaki N.

EMBO J 44 ( 3 ) 767 - 780 2025年2月

Ligand-independent function of β2-adrenergic receptor affects IgE-mediated Ca2+ influx in mast cells 査読

Nagao K, Yoshikawa S, Urakami H, Fujita Y, Komura A, Nakashima M, Oh-Hora M, Fujimura A, Hiyama TY, Naruse K, Morizane S, Tominaga M, Takamori K, Miyake S

Biochemical and Biophysical Research Communications 733 150595 - 150595 2024年11月

Direct Binding of Synaptopodin 2-Like Protein to Alpha-Actinin Contributes to Actin Bundle Formation in Cardiomyocytes 査読国際誌

Yamada H, Osaka H, Tatsumi N, Araki M, Abe T, Kaihara K, Takahashi K, Takashima E, Uchihashi T, Naruse K, Takei K

Cells 13 ( 16 ) 1373 - 1373 2024年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：MDPI AG

Synaptopodin 2-like protein (SYNPO2L) is localized in the sarcomere of cardiomyocytes and is involved in heart morphogenesis. However, the molecular function of SYNPO2L in the heart is not fully understood. We investigated the interaction of SYNPO2L with sarcomeric α-actinin and actin filaments in cultured mouse cardiomyocytes. Immunofluorescence studies showed that SYNPO2L colocalized with α-actinin and actin filaments at the Z-discs of the sarcomere. Recombinant SYNPO2La or SYNPO2Lb caused a bundling of the actin filaments in the absence of α-actinin and enhanced the α-actinin-dependent formation of actin bundles. In addition, high-speed atomic force microscopy revealed that SYNPO2La directly bound to α-actinin via its globular ends. The interaction between α-actinin and SYNPO2La fixed the movements of the two proteins on the actin filaments. These results strongly suggest that SYNPO2L cooperates with α-actinin during actin bundle formation to facilitate sarcomere formation and maintenance.

DOI： 10.3390/cells13161373

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Human heart-on-a-chip microphysiological system comprising endothelial cells, fibroblasts, and iPSC-derived cardiomyocytes 査読

Liu Y, Kamran R, Han X, Wang M, Li Q, Lai D, Naruse K, Takahashi K

Scientific Reports 14 ( 1 ) 18063 2024年8月

Celiac and superior mesenteric ganglia removal improves glucose tolerance and reduces pancreas islet size 査読

Xu S, Inoue M, Yoshimura Y, Kondoh K, Naruse K, Hiyama TY

Neuroscience Letters 837 137919 - 137919 2024年8月

Effect of mechanical stretching stimulation on maturation of human iPS cell-derived cardiomyocytes co-cultured with human gingival fibroblasts

Wang M, Idei H, Wang C, Liang Y, Liu Y, Matsuda Y, Takahashi K, Kamioka H, Naruse K

2023年12月

担当区分：最終著者記述言語：英語出版者・発行元：Cold Spring Harbor Laboratory

Abstract

In the realm of regenerative medicine, despite the various techniques available for inducing the differentiation of induced pluripotent stem (iPS) cells into cardiomyocytes, there remains a need to enhance the efficiency of this induction process. This study aimed to improve the differentiation efficiency of iPS-derived cardiomyocytes (iPS-CMs) by incorporating mechanical stretching. Human iPS cells were co-cultured with human gingival fibroblasts (HGF) on a polydimethylsiloxane (PDMS) stretch chamber, where mechanical stretching stimulation was applied during the induction of cardiomyocyte differentiation. The maturation of iPS-CMs was assessed using qRT-PCR, immunofluorescence staining, transmission electron microscopy, and contractility comparisons. Results indicated significantly elevated gene expression levels of cardiomyocyte markers (cTnT) and the mesodermal marker (Nkx2.5) in the stretch group compared to the control group. Fluorescent immunocytochemical staining revealed the presence of cardiac marker proteins (cTnT and HCN4) in both groups, with higher protein expression in the stretch group. Additionally, sarcomere length in the stretch group was notably larger than in the control group. A significant increase in the contractility of iPS-CMs was observed in the stretch group. These findings demonstrate that mechanical stretching stimulation enhances the maturity and differentiation efficiency of iPS-CMs co-cultured with fibroblasts.

DOI： 10.1101/2023.12.15.567696

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Development of lung tissue models and their applications 査読

Nalinrat Petpiroon, Woranan Netkueakul, Kanokwan Sukrak, Chen Wang, Yin Liang, Mengxue Wang, Yun Liu, Qiang Li, Rumaisa Kamran, Keiji Naruse, Sasitorn Aueviriyavit, Ken Takahashi

Life Sciences 334 122208 - 122208 2023年12月

Stretch‐induced reactive oxygen species contribute to the Frank–Starling mechanism 査読

Kaihara K, Kai H, Chiba Y, Naruse K, Iribe G

The Journal of Physiology 2023年4月

High hydrostatic pressure induces slow contraction in mouse cardiomyocytes 査読

Yamaguchi Y, Nishiyama M, Kai H, Kaneko T, Kaihara K, Iribe G, Takai A, Naruse K, Morimatsu M

Biophysical Journal 122 ( 1 ) 267 - 267 2023年1月

Live imaging of nitric oxide release in vascular endothelial cells in response to mechanical stimuli on an organ chip 査読

Takahashi K, Liu Y, Wang M, Liang Y, Naruse K

European Heart Journal 43 ( Supplement_22 ) 2022年10月

担当区分：最終著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Oxford University Press (OUP)

Abstract

Background

Nitric oxide (NO), released from vascular endothelial cells in response to mechanical stimuli, regulates cardiac contractility and are also involved in the prevention of the development of cardiac hypertrophy.

Purpose

To establish an experimental system for live observation of NO release in response to mechanical stimuli on an organ chip.

Methods

Organ chips, which we used for the development of a heart-on-a-chip in the previous study [1], were used.

We seeded 300,000 human umbilical vein endothelial cells on a stretchable elastic membrane coated with Matrigel of a chip channel. Shear stress was applied to the cells by increasing flow rate of a peristaltic pump connected to the chip channel (Figure 1A). Pressure stimulus was applied by hydrostatic pressure. Stretch stimulus was applied by suction to the side ports of a chip using an electric syringe pump (Figure 1B). Cells were stained with 10 μM 4,5-diaminofluorescein diacetate for fluorescent live NO imaging.

Results

Monolayers of the endothelial cells formed intercellular junctions confirmed by CD31 staining (Figure 1C, yellow). Apparent permeability, which was measured by Texas red dye (MW 3000), was maintained at a low level of ∼3x10–6 cm/s until day 30, suggested the formation of robust intercellular junction.

When the endothelial cells were subjected to a pressure stimulus of 60 mmHg for 60 s, NO release was observed that lasted for &gt;2 minutes (Figure 2A). A peak value of 1.46±1.08 (mean ± standard deviation) times the baseline was observed 271 s after the beginning of the pressure stimulus (n=251 cells). When the cells were subjected to a 1% stretch for 60 s, a peak value of 1.29±0.33 times the baseline was observed 105 s after the beginning of the stretch stimulus (Figure 2B). A shear stress of 0.01 dyn/cm2 hardly increased NO release (1.20±0.27 times the baseline, Figure 2C).

Conclusion

The system for live NO imaging in vascular endothelial cells in response to mechanical stimuli was established using organ-on-a-chip. The heart-on-a-chip with endothelial cells will be useful in elucidating the effects of mechanical stimulus such as hypertension on the contractile function and the remodeling of the heart.

Funding Acknowledgement

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Japan Society for the Promotion of Science

DOI： 10.1093/eurheartj/ehac544.3027

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High hydrostatic pressure induces slow contraction in mouse cardiomyocytes. 査読国際誌

Yamaguchi Y, Nishiyama M, Kai H, Kaneko T, Kaihara K, Iribe G, Takai A, Naruse K, Morimatsu M

Biophysical journal 2022年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Cardiomyocytes are contractile cells that regulate heart contraction. Ca2+ flux via Ca2+ channels activates actomyosin interactions, leading to cardiomyocyte contraction, which is modulated by physical factors (e.g., stretch, shear stress, and hydrostatic pressure). We evaluated the mechanism triggering slow contractions using a high-pressure microscope to characterize changes in cell morphology and intracellular Ca2+ concentration ([Ca2+]i) in mouse cardiomyocytes exposed to high hydrostatic pressures. We found that cardiomyocytes contracted slowly without an acute transient increase in [Ca2+]i, while a myosin ATPase inhibitor interrupted pressure-induced slow contractions. Furthermore, transmission electron microscopy showed that, although the sarcomere length was shortened upon the application of 20 MPa, this pressure did not collapse cellular structures such as the sarcolemma and sarcomeres. Our results suggest that pressure-induced slow contractions in cardiomyocytes are driven by the activation of actomyosin interactions without an acute transient increase in [Ca2+]i.

DOI： 10.1016/j.bpj.2022.07.016

PubMed

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Gravity sensing in plant and animal cells 査読

Takahashi K, Takahashi H, Furuichi T, Toyota M, Furutani-Seiki M, Kobayashi T, Watanabe-Takano H, Shinohara M, Numaga-Tomita T, Sakaue-Sawano A, Miyawaki A, Naruse K

npj Microgravity 7 ( 1 ) 2 2021年12月

担当区分：最終著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Science and Business Media LLC

Abstract

Gravity determines shape of body tissue and affects the functions of life, both in plants and animals. The cellular response to gravity is an active process of mechanotransduction. Although plants and animals share some common mechanisms of gravity sensing in spite of their distant phylogenetic origin, each species has its own mechanism to sense and respond to gravity. In this review, we discuss current understanding regarding the mechanisms of cellular gravity sensing in plants and animals. Understanding gravisensing also contributes to life on Earth, e.g., understanding osteoporosis and muscle atrophy. Furthermore, in the current age of Mars exploration, understanding cellular responses to gravity will form the foundation of living in space.

DOI： 10.1038/s41526-020-00130-8

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その他リンク： http://www.nature.com/articles/s41526-020-00130-8

Development of a human heart-on-a-chip model using induced pluripotent stem cells, fibroblasts and endothelial cells 査読

Liu Y, Wang M, Liang Y, Naruse K, Takahashi K

European Heart Journal 42 ( Supplement_11 ) 2021年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Oxford University Press (OUP)

Abstract

Background

The use of animal models in cardiovascular research is associated with two serious, intrinsic problems: inaccuracy in the extrapolation of data obtained from animals such as rodents due to different cardiac physiology and animal ethics.

Purpose

To develop an artificial human heart model for cardiovascular research using organ-on-a-chip technology and human cells

Methods

Organ chips made of silicone (polydimethylsiloxane) that have two microfluidic channels, a top channel and a bottom channel, separated by a 50-μm thick membrane with 7-μm pores hexagonally packed at 40-μm intervals (Figure 1), were used in this study.

We seeded 10,000 human umbilical vein endothelial cells on the membrane surface in the bottom channel to mimic the vasculature. Next, we seeded a mixture of 100,000 human-induced pluripotent stem cells (hiPSCs) and 50,000 human gingival fibroblasts on the membrane surface in the top channel (Figure 1). Human gingival fibroblasts facilitate cardiac differentiation of hiPSCs [1]. We performed the cardiac differentiation of hiPSCs using a previously described protocol [1]. Culture medium was perfused at a constant rate of 60 μl/h to maintain the culture.

Results

We observed spontaneous contraction of hiPSC-derived cardiomyocytes 20–26 days after the start of the differentiation protocol. Simultaneously, we conducted live intracellular calcium imaging using a fluorogenic calcium-sensitive dye, Cal-520 AM (5 μM in the culture medium). hiPSC-derived cardiomyocytes exhibited a periodic, coordinated pattern of calcium influx synchronised with their contraction under fluorescence microscopy (Figure 2A). Moreover, we found that the β-adrenergic agonist noradrenaline elevated the heart rate of hiPSC-derived cardiomyocytes on the organ chips in a dose-dependent manner (Figures 2A, B).

After observing the contraction and intracellular calcium influx of hiPSC-derived cardiomyocytes, we performed immunocytochemistry. Confocal microscopy indicated that the fluorescent signal obtained from anti-cardiac troponin T antibody staining in the top channel exhibited a typical striated pattern with 1.56±0.12-μm interval that reflected sarcomere structure (Figure 2C, yellow). Moreover, the fluorescent signal obtained from anti-CD31 antibody staining in the bottom channel exhibited a typical pattern at the boundary between cells, which is expected at the cell–cell junction of endothelial cells.

Conclusion

We developed a human heart-on-a-chip model that was confirmed by the functional response to noradrenaline and the histological evidence of sarcomere structure and vasculature, with a capability of live imaging. We expect that this model would be useful for examining the physiological function and for the pharmacological analysis of not only the normal heart but also the heart that reflects specific patient's pathophysiology using patient-derived hiPSCs.

Funding Acknowledgement

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Japan Society for the Promotion of Science Figure 1Figure 2

DOI： 10.1093/eurheartj/ehab724.3190

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Meta-Analysis-Assisted Detection of Gravity-Sensitive Genes in Human Vascular Endothelial Cells 査読

Yin Liang, Mengxue Wang, Yun Liu, Chen Wang, Ken Takahashi, Keiji Naruse

Frontiers in Cell and Developmental Biology 9 689662 2021年8月

担当区分：最終著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Frontiers Media SA

Gravity affects the function and maintenance of organs, such as bones, muscles, and the heart. Several studies have used DNA microarrays to identify genes with altered expressions in response to gravity. However, it is technically challenging to combine the results from various microarray datasets because of their different data structures. We hypothesized that it is possible to identify common changes in gene expression from the DNA microarray datasets obtained under various conditions and methods. In this study, we grouped homologous genes to perform a meta-analysis of multiple vascular endothelial cell and skeletal muscle datasets. According to the t-distributed stochastic neighbor embedding (t-SNE) analysis, the changes in the gene expression pattern in vascular endothelial cells formed specific clusters. We also identified candidate genes in endothelial cells that responded to gravity. Further, we exposed human umbilical vein endothelial cells (HUVEC) to simulated microgravity (SMG) using a clinostat and measured the expression levels of the candidate genes. Gene expression analysis using qRT-PCR revealed that the expression level of the prostaglandin (PG) transporter gene <italic>SLCO2A1</italic> decreased in response to microgravity, consistent with the meta-analysis of microarray datasets. Furthermore, the direction of gravity affected the expression level of <italic>SLCO2A1</italic>, buttressing the finding that its expression was affected by gravity. These results suggest that a meta-analysis of DNA microarray datasets may help identify new target genes previously overlooked in individual microarray analyses.

DOI： 10.3389/fcell.2021.689662

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Involvement of Transient Receptor Potential Vanilloid Channel 2 in the Induction of Lubricin and Suppression of Ectopic Endochondral Ossification in Mouse Articular Cartilage. 査読国際誌

Nakamoto H, Katanosaka Y, Chijimatsu R, Mori D, Xuan F, Yano F, Omata Y, Maenohara Y, Murahashi Y, Kawaguchi K, Yamagami R, Inui H, Taketomi S, Taniguchi Y, Kanagawa M, Naruse K, Tanaka S, Saito T

Arthritis & rheumatology (Hoboken, N.J.) 73 ( 8 ) 1441 - 1450 2021年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: Transient receptor potential vanilloid channel 2 (TRPV2) is a Ca2+ -permeable channel and plays a role in mediating intracellular Ca2+ current via mechanical stimuli. This study was undertaken to examine the expression and role of TRPV2 in adult articular cartilage and the development of osteoarthritis (OA). METHODS: We examined TRPV2 expression in mouse and human articular cartilage. We analyzed the development of OA in Col2a1-CreERt2 ;Trpv2fl/fl mice and Trpv2fl/fl littermates in the resection of the medial meniscus and medial collateral ligament model (n = 5 each), the destabilization of the medial meniscus model (n = 5 each), and the aging mouse model (n = 8-9 each). We examined marker protein expression in these joints, Ca2+ influx by mechanical stimuli, and downstream pathways in vitro. RESULTS: TRPV2 was expressed in mouse and human articular cartilage and ectopic ossification lesions. In all mouse models of OA examined, Col2a1-CreERt2 ;Trpv2fl/fl mice were observed to have enhanced degradation of articular cartilage accompanied by decreased expression of lubricin/Prg4, and marked formation of periarticular ectopic ossification. Mechanical stress-induced Ca2+ influx was decreased by Trpv2 knockout (KO). Prg4 induction by fluid-flow shear stress was diminished in Trpv2-KO mouse chondrocytes, and this was mediated by the Ca2+ /calmodulin-dependent protein kinase kinase-cyclic AMP response element binding protein axis. Hypertrophic differentiation was enhanced in Trpv2-KO mouse chondrocytes. Increased activity of calcineurin and nuclear translocation of nuclear factor in activated T cells 1 induced by fluid-flow shear stress or TRP agonist treatment was reversed by Trpv2 knockout. CONCLUSION: Our findings demonstrate regulation of articular cartilage by TRPV2 through Prg4 induction and suppression of ectopic ossification.

DOI： 10.1002/art.41684

PubMed

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Role of the TRPM4 channel in mitochondrial function, calcium release, and ROS generation in oxidative stress 査読

Chen Wang, Jian Chen, Mengxue Wang, Keiji Naruse, Ken Takahashi

Biochemical and Biophysical Research Communications 566 190 - 196 2021年8月

Production of TRPM4 knockout cell line using rat cardiomyocyte H9c2 査読

Chen Wang, Masakazu Maeda, Jian Chen, Mengxue Wang, Keiji Naruse, Ken Takahashi

MethodsX 8 101404 - 101404 2021年5月

The Mechanisms of the Development of Atherosclerosis in Prediabetes 査読

Yin Liang, Mengxue Wang, Chen Wang, Yun Liu, Keiji Naruse, Ken Takahashi

International Journal of Molecular Sciences 22 ( 8 ) 4108 - 4108 2021年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：MDPI AG

Lifestyle changes, such as overeating and underexercising, can increase the risk of prediabetes. Diabetes is one of the leading causes of atherosclerosis, and recently it became clear that the pathophysiology of atherosclerosis progresses even before the onset of diabetic symptoms. In addition to changes in platelets and leukocytes in the hyperglycemic state and damage to vascular endothelial cells, extracellular vesicles and microRNAs were found to be involved in the progression of prediabetes atherosclerosis. This review discusses the cellular and molecular mechanisms of these processes, with an intention to enable a comprehensive understanding of the pathophysiology of prediabetes and atherosclerosis.

DOI： 10.3390/ijms22084108

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