Language：English   Publishing type：Research paper (scientific journal)  

In vertebrates, sperm is generated in testicular tube-like structures called seminiferous tubules. The differentiation stages of spermatogenesis exhibit a dynamic spatiotemporal wavetrain pattern. There are two types of pattern-the vertical type, which is observed in mice, and the helical type, which is observed in humans. The mechanisms of this pattern difference remain little understood. In the present study, we used a three-species reaction-diffusion model to reproduce the wavetrain pattern observed in vivo. We hypothesized that the wavelength of the pattern in mice was larger than that in humans and undertook numerical simulations. We found complex patterns of helical and vertical pattern frequency, which can be understood by pattern selection using boundary conditions. From these theoretical results, we predicted that a small number of vertical patterns should be present in human seminiferous tubules. We then found vertical patterns in histological sections of human tubules, consistent with the theoretical prediction. Finally, we showed that the previously reported irregularity of the human pattern could be reproduced using two factors: a wider unstable wavenumber range and the irregular geometry of human compared with mouse seminiferous tubules. These results show that mathematical modeling is useful for understanding the pattern dynamics of seminiferous tubules in vivo.

DOI： 10.1007/s11538-021-00863-x

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1371/journal.pone.0240552

Language：English  

Pericytes (PCs) wrap around endothelial cells (ECs) and perform diverse functions in physiological and pathological processes. Although molecular interactions between ECs and PCs have been extensively studied, the morphological processes at the cellular level and their underlying mechanisms have remained elusive. In this study, using a simple cellular Potts model, we explored the mechanisms for EC wrapping by PCs. Based on the observed in vitro cell wrapping in three-dimensional PC-EC coculture, the model identified four putative contributing factors: preferential adhesion of PCs to the extracellular matrix (ECM), strong cell-cell adhesion, PC surface softness and larger PC size. While cell-cell adhesion can contribute to the prevention of cell segregation and the degree of cell wrapping, it cannot determine the orientation of cell wrapping alone. While atomic force microscopy revealed that PCs have a larger Young's modulus than ECs, the experimental analyses supported preferential ECM adhesion and size asymmetry. We also formulated the corresponding energy minimization problem and numerically solved this problem for specific cases. These results give biological insights into the role of PC-ECM adhesion in PC coverage. The modelling framework presented here should also be applicable to other cell wrapping phenomena observed in vivo.

DOI： 10.1098/rsif.2019.0739

Language：English   Publishing type：Research paper (scientific journal)  

Tight junctions (TJs) establish the epithelial barrier and are thought to form a membrane fence to regulate epithelial polarity, although the roles of TJs in epithelial polarity remain controversial. Claudins constitute TJ strands in conjunction with the cytoplasmic scaffolds ZO-1 and ZO-2 and play pivotal roles in epithelial barrier formation. However, how claudins and other TJ membrane proteins cooperate to organize TJs remains unclear. Here, we systematically knocked out TJ components by genome editing and show that while ZO-1/ZO-2-deficient cells lacked TJ structures and epithelial barriers, claudin-deficient cells lacked TJ strands and an electrolyte permeability barrier but formed membrane appositions and a macromolecule permeability barrier. Moreover, epithelial polarity was disorganized in ZO-1/ZO-2-deficient cells, but not in claudin-deficient cells. Simultaneous deletion of claudins and a TJ membrane protein JAM-A resulted in a loss of membrane appositions and a macromolecule permeability barrier and in sporadic epithelial polarity defects. These results demonstrate that claudins and JAM-A coordinately regulate TJ formation and epithelial polarity.

DOI： 10.1083/jcb.201812157

Language：English   Publishing type：Research paper (scientific journal)  

Precise cell division control is critical for developmental patterning. For the differentiation of a functional stoma, a cellular valve for efficient gas exchange, the single symmetric division of an immediate precursor is absolutely essential. Yet, the mechanism governing this event remains unclear. Here we report comprehensive inventories of gene expression by the Arabidopsis bHLH protein MUTE, a potent inducer of stomatal differentiation. MUTE switches the gene expression program initiated by SPEECHLESS. MUTE directly induces a suite of cell-cycle genes, including CYCD5;1, in which introduced expression triggers the symmetric divisions of arrested precursor cells in mute, and their transcriptional repressors, FAMA and FOUR LIPS. The regulatory network initiated by MUTE represents an incoherent type 1 feed-forward loop. Our mathematical modeling and experimental perturbations support a notion that MUTE orchestrates a transcriptional cascade leading to a tightly restricted pulse of cell-cycle gene expression, thereby ensuring the single cell division to create functional stomata. Stomata, small valves on the plant epidermis, are made of two guard cells surrounding a pore. Han et al. show that the transcription factor MUTE orchestrates gene regulatory circuits to switch cells to a differentiation state, then ensures that only a single symmetric division occurs to create a functional stoma.

DOI： 10.1016/j.devcel.2018.04.010

Language：English   Publishing type：Research paper (scientific journal)  

Angiogenesis is a multicellular phenomenon driven by morphogenetic cell movements. We recently reported morphogenetic vascular endothelial cell (EC) behaviors to be dynamic and complex. However, the principal mechanisms orchestrating individual EC movements in angiogenic morphogenesis remain largely unknown. Here we present an experiment-driven mathematical model that enables us to systematically dissect cellular mechanisms in branch elongation. We found that cell-autonomous and coordinated actions governed these multicellular behaviors, and a cell-autonomous process sufficiently illustrated essential features of the morphogenetic EC dynamics at both the single-cell and cell-population levels. Through refining our model and experimental verification, we further identified a coordinated mode of tip EC behaviors regulated via a spatial relationship between tip and follower ECs, which facilitates the forward motility of tip ECs. These findings provide insights that enhance our mechanistic understanding of not only angiogenic morphogenesis, but also other types of multicellular phenomenon.

DOI： 10.1016/j.celrep.2015.10.051

Language：English   Publishing type：Research paper (scientific journal)  

Angiogenesis is a complex process, which is accomplished by reiteration of modules such as sprouting, elongation and bifurcation, that configures branching vascular networks. However, details of the individual and collective behaviors of vascular endothelial cells (ECs) during angiogenic morphogenesis remain largely unknown. Herein, we established a time-lapse imaging and computer-assisted analysis system that quantitatively characterizes behaviors in sprouting angiogenesis. Surprisingly, ECs moved backwards and forwards, overtaking each other even at the tip, showing an unknown mode of collective cell movement with dynamic 'cell-mixing'. Mosaic analysis, which enabled us to monitor the behavior of individual cells in a multicellular structure, confirmed the 'cell-mixing' phenomenon of ECs that occurs at the whole-cell level. Furthermore, an in vivo EC-tracking analysis revealed evidence of cell-mixing and overtaking at the tip in developing murine retinal vessels. In parametrical analysis, VEGF enhanced tip cell behavior and directed EC migration at the stalk during branch elongation. These movements were counter-regulated by EC-EC interplay via γ-secretase-dependent Dll4-Notch signaling, and might be promoted by EC-mural cell interplay. Finally, multiple regression analysis showed that these molecule-mediated tip cell behaviors and directed EC migration contributed to effective branch elongation. Taken together, our findings provide new insights into the individual and collective EC movements driving angiogenic morphogenesis. The methodology used for this analysis might serve to bridge the gap in our understanding between individual cell behavior and branching morphogenesis.

DOI： 10.1242/dev.068023

Language：English   Publishing type：Research paper (scientific journal)  

Strength of inflammatory stimuli during the early expansion phase plays a crucial role in the effector versus memory cell fate decision of CD8⁺ T cells. But it is not known how early lymphocyte distribution after infection has an impact on this process. We demonstrate that the chemokine receptor CXCR3 is involved in promoting CD8⁺ T cell commitment to an effector fate rather than a memory fate by regulating T cell recruitment to an antigen/inflammation site. After systemic viral or bacterial infection, the contraction of CXCR3^-/- antigen-specific CD8⁺ T cells is significantly attenuated, resulting in massive accumulation of fully functional memory CD8+ T cells. Early after infection, CXCR3^-/- antigen-specific CD8+ T cells fail to cluster at the marginal zone in the spleen where inflammatory cytokines such as IL-12 and IFN-α are abundant, thus receiving relatively weak inflammatory stimuli. Consequently, CXCR3^-/- CD8+ T cells exhibit transient expression of CD25 and preferentially differentiate into memory precursor effector cells as compared with wild-type CD8⁺ T cells. This series of events has important implications for development of vaccination strategies to generate increased numbers of antigen-specific memory CD8⁺ T cells via inhibition of CXCR3-mediated T cell migration to inflamed microenvironments.

DOI： 10.1084/jem.20102101

Event date： 2023.12

Presentation type：Oral presentation (general)  

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Event date： 2023.12

Presentation type：Symposium, workshop panel (public)  

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Event date： 2023.10 - 2023.11

Presentation type：Oral presentation (general)  

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Event date： 2023.10 - 2023.11

Presentation type：Symposium, workshop panel (nominated)  

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Event date： 2023.9

Language：Others  

Country：Other  

Mathematical model of segmented nucleus formation in human neutrophils

Event date： 2023.9

Presentation type：Oral presentation (general)  

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Event date： 2023.9

Presentation type：Poster presentation  

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Event date： 2022.5 - 2022.6

Language：Others  

Country：Other  

Preference of pericytes for vascular junctions by three-dimensional topography

Event date： 2021.12

Language：Others  

Country：Other  

Event date： 2021.9

Language：Others  

Country：Other  

Event date： 2021.6

Language：Japanese  

Venue：オンライン   Country：Japan  

Event date： 2020.6

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2019.11

Language：Others  

Country：Other  

Event date： 2019.9

Language：Others  

Country：Other  

Event date： 2019.5

Language：Others  

Country：Other  

Event date： 2018.6

Language：Others  

Country：Other  

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Language：Others  

Country：Other  

Language：Japanese  

Language：Japanese  

Presentation type：Public lecture, seminar, tutorial, course, or other speech  

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