Biology subjects

Matsuoka, M.

Publications and source records attributed to Matsuoka, M..

13 recordsLinked to original sources

bioRxiv2026

Desialylated platelets promote hepatocyte proliferation via the ERK1/2 signaling pathway

Platelets are increasingly recognized as active regulators of tissue repair and liver regeneration beyond their classical roles in hemostasis and thrombosis. Loss of terminal sialic acid from platelet surface glycoproteins, a process known as desialylation, occurs during platelet aging or activation and has been linked to platelet clearance via the asialoglycoprotein receptor (ASGPR) on hepatocytes. However, the mechanisms by which desialylated platelets (D-plts) directly stimulate hepatocyte proliferation remain poorly understood. This study aimed to elucidate the proliferative effects of D-plts on hepatocytes and to identify the underlying signaling mechanisms. D-plts were generated and co-cultured with hepatocyte models exhibiting low or absent levels of asialoglycoprotein receptor 1 (ASGPR1) expression, including HepG2 cells, HuH-7 cells, and human chemically induced liver progenitors. Hepatocyte proliferation was assessed, and the roles of platelet-derived factors and downstream signaling pathways were investigated. Co-culture with D-plts significantly increased hepatocyte proliferation in all three cell models compared with the corresponding controls. Moreover, supernatants derived from stimulated D-plts also significantly enhanced hepatocyte proliferation, suggesting that soluble platelet-derived factors contribute to this effect. Mechanistically, the proliferative effects were mediated predominantly through the ERK1/2 signaling pathway rather than the JAK-STAT pathway in both hepatocytes co-cultured with D-plts and those treated with D-plt-derived supernatants. In conclusion, our findings demonstrate that D-plts directly promote hepatocyte proliferation through an ASGPR-independent pathway, in which ERK1/2 signaling plays a central role. These results highlight a novel mechanism through which platelet desialylation may contribute to liver regeneration. Graphical Abstract(A) Desialylated platelets are readily activated and release increased amounts of EGF, promoting hepatocyte proliferation via the EGF-ERK signaling pathway. (B) Normal platelets show lower reactivity and reduced EGF release than desialylated platelets, resulting in weaker hepatocyte proliferation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/740293v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@d8eb25org.highwire.dtl.DTLVardef@135e644org.highwire.dtl.DTLVardef@1a0a924org.highwire.dtl.DTLVardef@c092e9_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2026

Animal model of leprous neuritis using transfer of sensitized lymphocytes into M. leprae-inoculated nude mice

BackgroundLeprosy is curable with multidrug therapy, but preventing peripheral neuropathy remains challenging. In leprosy, reversal reactions (Type 1 reactions) are characterized by sudden enhanced cell-mediated immunity against Mycobacterium leprae (M. leprae), leading to acute neuritis that may cause irreversible nerve damage, paralysis, sensory impairment, and muscle atrophy. Armadillo and nude mouse models are used to study M. leprae infection, but detailed neuropathological models for immune-mediated reactions in leprosy are lacking. This study aimed to establish a reproducible animal model to analyze leprous neuritis pathogenesis. Methodology/Principal FindingsBALB/c nude mice were inoculated with M. leprae and six months later received transfers of naive CD4+ cells, sensitized CD4+ cells, or sensitized whole spleen cells from BALB/c mice. Histological and quantitative analyses were performed four weeks post-transfer. Mice that received transfer of sensitized CD4+ cells or sensitized spleen cells exhibited footpad swelling up to 88% greater than in animals with no cell transfer. Mice that received the sensitized cells also had massive inflammatory cell infiltration into nerve fascicles. Quantitative imaging confirmed a significant reduction in the percentage of myelinated area in mice that received transfer of sensitized CD4+ (p < 0.05) or whole spleen cells (p < 0.01) compared to control mice with no transfer. Furthermore, bacterial fragmentation within the endoneurium coincided with myelinated axon destruction, indicating that the immune response targeted bacilli but simultaneously damaged nerve structures. Conclusions/SignificanceThis study successfully reproduced leprous peripheral neuritis that resembles the reversal reaction in humans. The findings indicate that CD4+ cells are primary drivers of inflammation, whereas interactions between multiple immune cell populations in whole spleen cell transfers further exacerbate disease pathology. This model confirms that host immune responses are crucial for nerve injury progression. This model provides a valuable tool for investigating neuroprotective therapies to prevent permanent disability in patients with leprosy. Author SummaryAlthough leprosy can be treated as an infectious disease, many patients still suffer from permanent peripheral nerve damage, known as leprous neuritis. A particularly dangerous condition called the "reversal reaction" occurs when the immune system of an infected individual suddenly overreacts, causing severe acute inflammation in the nerves. Without prompt treatment, this inflammatory response can result in irreversible nerve damage, paralysis, and muscle atrophy. In this study, we developed a new animal model using "nude mice", which lack their own T-cells, to understand how this damage happens. We infected these mice with leprosy bacteria and then transferred specific immune cells, specifically sensitized CD4+ T cells, isolated from M. leprae-immunized mice. The results showed that this transfer triggered significant footpad swelling and caused inflammatory cells to invade the nerve fascicles. Most importantly, we observed a significant reduction in myelin, the protective coating that promotes nerve signaling. These findings confirm that nerve damage is largely driven by the hosts own immune response attempting to clear the bacteria. By successfully recreating this reaction, our research provides a vital tool for developing new therapies aimed at preventing permanent disability and protecting the physical functions of patients.

immunology↗

bioRxiv2025

Machine Learning-based Identification and Characterization of High-risk Carriers of HTLV-1-Associated Myelopathy (HAM)

HTLV-1-associated myelopathy (HAM) develops in a part of HTLV-1-infected individuals while most of the individuals remain asymptomatic. This complicates the identification of HTLV-1 carriers at elevated risk. In this study, we integrated HTLV-1 proviral load and antibody titers against Tax, Env, Gag p15, p19, and p24 proteins in a machine learning (ML) framework to identify and characterize high-risk individuals likely to develop HAM. We stratified asymptomatic carrier samples employing an anomaly detection model. We further developed and validated classifier models capable of distinguishing three clinical subgroups, carrier, ATL, and HAM for assessing the anomaly carrier samples as unseen test data. With most anomaly carrier samples ([~]76.47%) predicted as HAM, further statistical and interpretative analysis revealed the HAM-like characteristics of the anomaly carrier samples indicating elevated risk. Additionally, significant heterogeneity in immune response was observed among other asymptomatic carriers. Our machine learning-based approach offers a novel and insightful tool for identifying and evaluating high-risk characteristics for HAM, providing a holistic view of the complex immune dynamics of asymptomatic carriers of HTLV- 1.

systems biology↗

bioRxiv2024

Retinoid-impregnated nanoparticles enable control of bone growth by site-specific modulation of endochondral ossification in mice

Growth-plate (GP) injures in limbs and other sites can impair GP function and cause deceleration of bone growth, leading to progressive bone lengthening imbalance, deformities and/or physical discomfort, decreased motion and pain. At present, surgical interventions are the only means available to correct these conditions by suppressing the GP activity in the unaffected limb and/or other bones in the ipsilateral region. Here, we aimed to develop a pharmacologic treatment of GP growth imbalance that involves local application of nanoparticles-based controlled release of a selective retinoic acid nuclear receptor gamma (RAR{gamma}) agonist drug. When RAR{gamma} agonist-loaded nanoparticles were implanted near the medial and lateral sides of proximal tibial growth plate in juvenile C57BL/6j mice, the GP underwent involution and closure. Overall tibia length was shortened compared to the contralateral element implanted with drug-free control nanoparticles. Importantly, when the RAR{gamma} agonist nanoparticles were implanted on the lateral side only, the adjacent epiphysis tilted toward the lateral site, leading to apical angulation of the tibia. In contrast to the local selectivity of these responses, systemic administration of RAR{gamma} agonists led to GP closure at many sites, inhibiting skeletal growth over time. Agonists for RAR and RAR{beta} elicited no obvious responses over parallel regimens. Our findings provide novel evidence that RAR{gamma} agonist-loaded nanoparticles can control activity, function and directionality of a targeted GP, offering a potential and clinically-relevant alternative or supplementation to surgical correction of limb length discrepancy and angular deformities. Lay summaryGrowth-plates (physes), which are cartilage tissues near the ends of bones, support normal bone growth in children. Growth plate injures in limbs and other sites can impair growth plate function, leading to inhibited or imbalanced bone growth, skeletal deformities, decreased motion, discomfort or pain. At present, surgical interventions are the only means available to correct these conditions. Here, we aimed to develop a pharmacologic treatment for bone growth imbalance. Nanoparticles loaded with a selective agonist for the retinoic acid nuclear receptor gamma were prepared and implanted near the tibial growth plate in juvenile mice. The growth plate underwent involution and closure, and overall tibia length was shortened compared to the contralateral element implanted with drug-free control nanoparticles. Importantly, when the same drug nanoparticles were implanted in only one side of the tibia, the tibia was tilted toward the injection site. Our findings provide novel evidence that retinoic acid receptor gamma agonist-loaded nanoparticles can control activity, function and directionality of a targeted growth plate, offering a potential and clinically-relevant alternative or supplementation to surgical correction of limb length imbalances and deformities.

pharmacology and toxicology↗

bioRxiv2024

JunB-HBZ nuclear translocation by TGF-beta is a key driver in HTLV-1-mediated leukemogenesis

The HTLV-1 bZIP factor (HBZ) gene, which is the only viral gene conserved and consistently expressed in all adult T-cell leukemia-lymphoma (ATL) cases, is critical for ATL oncogenesis. Although HBZ protein is found in both the nucleus and the cytoplasm, the dynamics of HBZ protein localization and its contribution to oncogenesis have not been fully elucidated. In this study, we analyzed the subcellular expression pattern of HBZ in primary HTLV-1-infected T cells from asymptomatic carriers and leukemic cells of ATL patients using the Proximity Ligation Assay. Nuclear localization of HBZ protein was significantly higher in fresh ATL cells than in HTLV-1-infected cells from carriers. Importantly, translocation of HBZ protein from the cytoplasm to the nucleus after TGF-{beta} activation was observed in ATL patients, but not in HTLV-1 carriers. In ATL cells, the cellular transcription factors JunB and pSmad3 interact with HBZ and facilitate its nuclear translocation upon TGF-{beta} stimulation. JUNB knockdown inhibits cell proliferation in vitro and in vivo and promotes apoptosis in ATL cells but not in HTLV-1-infected non-leukemic cells, indicating that JunB has important roles in maintaining ATL cells. In conclusion, TGF-{beta}-induced nuclear translocation of HBZ-JunB complexes is associated with ATL oncogenesis.

microbiology↗

bioRxiv2023

Articular cartilage corefucosylation regulates tissue resilience in osteoarthritis

This study aimed to investigate the glycan structural changes that occur before histological degeneration in osteoarthritis (OA) and to determine the mechanism by which these glycan conformational changes affect cartilage degeneration. An OA model was established in rabbits using mannosidase injection, which reduced high-mannose type N-glycans and led to cartilage degeneration. Further analysis of glycome in human OA cartilage identified specific corefucosylated N-glycan expression patterns. Inhibition of N-glycan corefucosylation resulted in unrecoverable cartilage degeneration, while cartilage-specific blocking of corefucosylation led to accelerated development of aging-associated and instability-induced OA models. We conclude that 1,6 fucosyltransferase is required postnatally to prevent preosteoarthritic deterioration of articular cartilage. These findings provide a novel definition of early OA and identify glyco-phenotypes of OA cartilage, which may distinguish individuals at higher risk of progression.

cell biology↗

bioRxiv2023

Host-Microbiome Associations in Saliva Predict COVID-19 Severity

Established evidence indicates that oral microbiota plays a crucial role in modulating host immune responses to viral infection. Following Severe Acute Respiratory Syndrome Coronavirus 2 - SARS-CoV-2 - there are coordinated microbiome and inflammatory responses within the mucosal and systemic compartments that are unknown. The specific roles that the oral microbiota and inflammatory cytokines play in the pathogenesis of COVID-19 are yet to be explored. We evaluated the relationships between the salivary microbiome and host parameters in different groups of COVID-19 severity based on their Oxygen requirement. Saliva and blood samples (n = 80) were collected from COVID-19 and from non-infected individuals. We characterized the oral microbiomes using 16S ribosomal RNA gene sequencing and evaluated saliva and serum cytokines using Luminex multiplex analysis. Alpha diversity of the salivary microbial community was negatively associated with COVID-19 severity. Integrated cytokine evaluations of saliva and serum showed that the oral host response was distinct from the systemic response. The hierarchical classification of COVID-19 status and respiratory severity using multiple modalities separately (i.e., microbiome, salivary cytokines, and systemic cytokines) and simultaneously (i.e., multi-modal perturbation analyses) revealed that the microbiome perturbation analysis was the most informative for predicting COVID-19 status and severity, followed by the multi-modal. Our findings suggest that oral microbiome and salivary cytokines may be predictive of COVID-19 status and severity, whereas atypical local mucosal immune suppression and systemic hyperinflammation provide new cues to understand the pathogenesis in immunologically naive populations. Significance StatementThe oral mucosa is one of the first sites encountered by bacterial and viral infections, including SARS-CoV-2. It consists of a primary barrier occupied by a commensal oral microbiome. The primary function of this barrier is to modulate immunity and provide protection against invading infection. The occupying commensal microbiome is an essential component that influences the immune systems function and homeostasis. The present study showed that the host oral immune response performs unique functions in response to SARS-CoV-2 when compared to systemic responses during the acute phase. We also demonstrated that there is a link between oral microbiome diversity and COVID-19 severity. Additionally, the salivary microbiome was predictive of not only disease status but also severity.

immunology↗

bioRxiv2022

Dissecting the cell of origin of aberrant SALL4 expression in myelodysplastic syndrome

Myelodysplastic syndrome (MDS) is a group of heterogeneous diseases characterized by cytologic dysplasia and cytopenias resulting from ineffective hematopoiesis. Oncofetal protein SALL4 is a known oncogene in MDS and its baseline expression level serves as a prognostic biomarker for MDS at the time of diagnosis. In addition, a recent study showed that SALL4 upregulation following hypomethylating agent treatment in MDS patients correlates with poor outcomes. Despite its important mechanistic and diagnostic significance, the cellular identity of bone marrow cells with aberrant SALL4 expression in MDS patients remains unknown. In this study, we analyzed MDS bone marrow cells on single cell level by mass cytometry (CyTOF) and found that SALL4 was mainly aberrantly expressed in the hematopoietic stem and progenitor cells (HSPC) as well as myeloid lineages. Within the HSPC population from MDS patients, SALL4 and p53 were co-expressed, with the highest co-expressing clones harboring pathogenic TP53 mutations. Overall, our study characterizes for the first time the aberrant SALL4 expression in primary MDS patient samples at a single-cell level. Further studies on the SALL4/p53 network for in-depth mechanistic investigation are needed in the future. Key PointsSALL4 expression in various MDS BM cells confirmed by mass cytometry (CyTOF). SALL4 and p53 double positive cells were predominantly found in the hematopoietic stem and progenitor cell (HSPC) population and associated with pathogenic TP53 mutation status.

cell biology↗

bioRxiv2022

Reprogramming of lactate metabolism is linked to the oncogenesis of the virus-induced leukemia

Acceleration of glycolysis is a common trait of cancer. A key metabolite, lactate, is properly secreted from cancer cells, since its accumulation is toxic. Here, we report that a viral oncogene, HTLV-1 bZIP factor (HBZ), bimodally upregulates TAp73 to promote lactate excretion from adult T-cell leukemia-lymphoma (ATL) cells. HBZ protein binds to EZH2 and reduces its occupancy of the TAp73 promoter. Meanwhile, HBZ RNA activates TAp73 transcription via the BATF3-IRF4 machinery. TAp73 upregulates the lactate transporters MCT1 and MCT4. Inactivation of TAp73 leads to intracellular accumulation of lactate, inducing cell death in ATL cells. Furthermore, TAp73 knockout diminished development of inflammation in HBZ-transgenic mice. An MCT1/4 inhibitor, syrosingopine, decreased the growth of ATL cells in vitro and in vivo. MCT1/4 expression was positively correlated with TAp73 in many cancers, and their upregulations were associated with dismal prognosis. Activation of the TAp73-MCT1/4 pathway could be a common mechanism contributing to oncogenesis.

cancer biology↗

bioRxiv2021

A small molecule, ACAi-028, with anti-HIV-1 activity targets a novel hydrophobic pocket on HIV-1 capsid

The human immunodeficiency virus type 1 (HIV-1) capsid (CA) is an essential viral component of HIV-1 infection, and an attractive therapeutic target for antivirals. We report that a small molecule, ACAi-028, inhibits HIV-1 replication by targeting a hydrophobic pocket in the N-terminal domain of CA (CA-NTD). ACAi-028 is one of more than 40 candidate anti-HIV-1 compounds identified by in silico screening and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Our binding model showed that ACAi-028 interacts with the Q13, S16, and T19 amino acid residues, via hydrogen bonds, in the targeting pocket of CA-NTD. Using recombinant fusion methods, TZM-bl, time-of-addition, and colorimetric reverse transcriptase (RT) assays, the compound was found to exert anti-HIV-1 activity in the early stage between a reverse transcriptase inhibitor, azidothymidine (AZT), and an integrase inhibitor, raltegravir (RAL), without any effect on RT activity, suggesting that this compound may affect HIV-1 core disassembly (uncoating). Moreover, electrospray ionization mass spectrometry (ESI-MS) also showed that the compound binds directly and non-covalently to the CA monomer. CA multimerization and thermal stability assays showed that ACAi-028 decreased CA multimerization and thermal stability via S16 or T19 residues. ImportanceThese results indicate that ACAi-028 is a novel CA inhibitor that binds to the novel hydrophobic pocket of CA-NTD. This study demonstrates that a compound targeting the new hydrophobic pocket is a promising anti-HIV-1 inhibitor. The findings presented here may offer the development of a novel class of anti-viral agents that can be used, providing HIV-1 patients with more options for Anti-retroviral therapy (ART) treatment. Despite many years of successful pharmaceutical developments in the area of anti-retroviral therapy, the prevalence of drug-resistant mutations in HIV-1, necessitates the continued development of novel agents, such as ACAi-028.

microbiology↗

bioRxiv2019

A unique conformational escape reaction of HIV-1 against an allosteric integrase inhibitor

HIV-1 integrase (IN) contributes to HIV-1 RNA binding, which is required for viral maturation. Non-catalytic site integrase inhibitors (NCINIs) have been developed as allosteric IN inhibitors, which perform anti-HIV-1 activity by disrupting IN multimerization. Here, we show that IN undergoes a novel conformational alteration to escape from NCINIs. We observed that NCINI-resistant HIV-1 variants have accumulated amino acid (AA) mutations in the IN-encoding region. We employed HPLC and thermal stability assays to show that the AA mutations affect the folding and dimerization interface of the IN catalytic core domains, resulting in severely decreased multimerization of full-length IN proteins (IN under-multimerization). The under-multimerization of IN was finally restored by HIV-1 RNA in the viral particles. Our study demonstrates that HIV-1 countervails NCINIs by IN under-multimerization as a novel escape mechanism. Our findings provide information on the understanding of IN multimerization and influence the development of unique anti-HIV-1 strategies.

microbiology↗

bioRxiv2019

Efficient horizontal transmission without viral super-spreaders may cause the high prevalence of STLV-1 infection in Japanese macaques

AbstractsSimian T-cell leukemia virus type-1 (STLV-1) is disseminated among various non-human primate species and is closely related to human T-cell leukemia virus type-1 (HTLV-1), the causative agent of adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis. Notably, the prevalence of STLV-1 infection in Japanese macaques (JMs) is estimated to be much greater than that in other non-human primates; however, the mechanism and mode of STLV-1 transmission remain unknown. We hypothesized that a substantial proportion of infected macaques may play a critical role as viral super-spreaders for efficient inter-individual transmission leading to the high prevalence of infection. To address this, we examined a cohort of 280 JMs reared in a free-range facility for levels of anti-STLV-1 antibody titers (ABTs) and STLV-1 proviral loads (PVLs). We found that the prevalence of STLV-1 in the cohort reached up to 65% (180/280), however, the ABTs and PVLs were normally distributed with mean values of 4076 and 0.62%, respectively, which were comparable to those of HTLV-1-infected humans. Contrary to our expectations, we did not observe the macaques with abnormally high PVLs and poor ABTs, and therefore, the possibility of viral super-spreaders was unlikely. Results from further analyses regarding age-dependent changes in STLV-1 prevalence and a longitudinal follow-up of STLV-1 seroconversion strongly suggest that frequent horizontal transmission is a major route of STLV-1 infection, probably due to the unique social ecology of JMs associated with environmental adaptation.\n\nImportanceWe investigated the cause of the high prevalence of STLV-1 infection in the studied JMs cohort. Contrary to our expectations, the potential viral super-spreaders as shown by abnormally high PVLs and poor ABTs were not observed among the JMs. Rather, the ABTs and PVLs among the infected JMs were comparable to those of HTLV-1-infected humans although the prevalence of HTLV-1 in humans is much less than the macaques. Further analyses demonstrate that the prevalence drastically increased over one year of age and most of these animals over 6 years of age were infected with STLV-1, and that in the longitudinal follow-up study frequent seroconversion occurred in not only infants but also in juvenile and adult seronegative monkeys (around 20% per year). This is the first report showing that frequent horizontal transmission without viral super-spreaders may cause high prevalence of STLV-1 infection in JMs.

microbiology↗

bioRxiv2018

Long noncoding RNA ANRIL supports proliferation of adult T-cell leukemia cells through cooperation with EZH2

Adult T-cell leukemia (ATL) is a highly aggressive T-cell malignancy induced by human T-cell leukemia virus type 1 (HTLV-1) infection. Long noncoding RNA (lncRNA) plays a critical role in the development and progression of multiple human cancers. However, the function of lncRNA on HTLV-1-induced oncogenesis has not been elucidated. In the present study, we show that the expression of the lncRNA ANRIL was elevated in HTLV-1 infected cell lines and clinical ATL samples. E2F1 induced ANRIL transcription by enhancing its promoter activity. Knocking down of ANRIL in ATL cells repressed cellular proliferation and increased apoptosis in vitro and in vivo. As a mechanism for these actions, we found that ANRIL targeted EZH2, and activated the NF-{kappa}B pathway in ATL cells. This activation was independent of the histone methyltransferase (HMT) activity of EZH2, but required the formation of an ANRIL/EZH2/p65 ternary complex. Chromatin immunoprecipitation assay revealed that ANRIL/EZH2 enhanced p65 DNA binding capability. In addition, we observed that ANRIL/EZH2 complex repressed p21/CDKN1A transcription through H3K27 trimethylation of the p21/CDKN1A promoter. Taken together, our results implicate that lncRNA ANRIL, by cooperating with EZH2, supports the proliferation of HTLV-1 infected cells, which is thought to be critical for oncogenesis.\n\nIMPORTANCEHuman T-cell leukemia virus type 1 (HTLV-1) is the pathogen that causes adult T-cell leukemia (ATL), which is a unique malignancy of CD4+ T cells. A role for long noncoding RNA (lncRNA) in HTLV-1-mediated cellular transformation has not been described. In this study, we demonstrated that lncRNA ANRIL was important for maintaining proliferation of ATL cells in vitro and in vivo. ANRIL was shown to activate NF-{kappa}B signaling through forming a ternary complex with EZH2 and p65. Further, epigenetic inactivation of p21/CDKN1A was involved in the oncogenic function of ANRIL. To the best of our knowledge, this is the first study to address the regulatory role of the lncRNA ANRIL in ATL and provides an important clue to prevent or treat HTLV-1 associated human diseases.

cancer biology↗