Biology subjects

Tada, S.

Publications and source records attributed to Tada, S..

5 recordsLinked to original sources

bioRxiv2025

Proteinase 3 is involved in presepsin production through neutrophil extracellular trap phagocytosis by macrophages

Presepsin (P-SEP), a soluble subtype of CD14, has been widely reported as a useful biomarker for sepsis in clinical studies. However, the cytological mechanism underlying its production remains poorly understood. Previous research has demonstrated that P-SEP is generated when M1 macrophages (M1 M{Phi}s) phagocytose neutrophil extracellular traps (NETs) and degrade internalized CD14. In this study, we demonstrated that M1 M{Phi}s phagocytose NETs and that proteinase 3 (PR3) within M1 M{Phi}s degrades NET-derived CD14, resulting in the production of P-SEP. Furthermore, we observed a strong correlation between the amount of NETs and P-SEP levels, indicating that NET phagocytosis is a key process in P-SEP generation. Our findings also suggest that PR3 released extracellularly along with NETs may degrade CD14 in plasma, contributing to elevated P-SEP levels. This mechanism may contribute to increased P-SEP concentrations observed in autoimmune diseases associated with NET accumulation, proposing P-SEP as a potential biomarker of disease activity beyond sepsis.

cell biology↗

bioRxiv2024

Zbtb38 inhibits apoptosis by transcriptionally regulating XIAP expression

The X-linked inhibitor of apoptosis protein (XIAP) is a key suppressor of apoptosis, crucial for cellular differentiation, embryogenesis, and cancer progression. However, its upstream regulatory mechanisms remain poorly understood. Here, we demonstrate that the zinc finger transcription factor Zbtb38, a negative regulator of apoptosis, modulates XIAP expression in both loss- and gain-of-function experiments, irrespective of p53 expression. Notably, XIAP overexpression rescues the apoptosis induced by Zbtb38 knockdown, indicating that Zbtb38-associated apoptosis is at least partially XIAP-dependent. Mechanistically, Zbtb38 binds to E-box motifs within upstream regulatory regions of XIAP and activates its transcription. During embryonic stem (ES) cell differentiation and embryogenesis, Zbtb38 depletion increases apoptosis and reduces XIAP and Bcl-2 expression, underscoring their functional relevance in these processes. Analysis of human tumor datasets reveals a strong positive correlation between ZBTB38 and XIAP expression, with elevated ZBTB38 levels associated with high-grade malignancies. Furthermore, Zbtb38 knockdown induces apoptosis in cancer cells with reduced XIAP expression, regardless of p53 expression. Collectively, these findings uncover a novel Zbtb38-XIAP axis that regulates apoptosis during cellular differentiation, development, and oncogenesis, and highlight its therapeutic potential in XIAP-driven and p53-deficient tumors.

cell biology↗

bioRxiv2022

A novel micro-ECoG recording method for recording multisensory neural activity from the parietal to temporal cortexes in mice

Characterization of inter-regional interactions in brain is essential for understanding the mechanism relevant to normal brain function and neurological disease. The recently developed flexible micro ()-electrocorticography (ECoG) device is one prominent method used to examine large-scale cortical activity across multiple regions. The sheet-shaped ECoG electrodes arrays can be placed on a relatively wide area of cortical surface beneath the skull by inserting the device into the space between skull and brain. Although rats and mice are useful tools for neuroscience, current ECoG recording methods in these animals are limited to the parietal region of cerebral cortex. Recording cortical activity from the temporal region of cortex in mice has proven difficult because of surgical barriers created by the skull and surrounding temporalis muscle anatomy. Here, we developed a sheet-shaped 64-channel ECoG device that allows access to the mouse temporal cortex, and we determined the factor determining the appropriate bending stiffness for the ECoG electrode array. We also established a surgical technique to implant the electrode arrays into the epidural space over a wide area of cerebral cortex covering from the barrel field to olfactory (piriform) cortex, which is the deepest region of the cerebral cortex. Using histology and computed tomography (CT) images, we confirmed that the tip of the ECoG device reached to the most ventral part of cerebral cortex without causing noticeable damage to the brain surface. Moreover, the device simultaneously recorded somatosensory and odor stimulus-evoked neural activity from dorsal and ventral parts of cerebral cortex in awake and anesthetized mice. These data indicate that our ECoG device and surgical techniques enable the recording of large-scale cortical activity from the parietal to temporal cortex in mice, including somatosensory and olfactory cortices. This system will provide more opportunities for the investigation of physiological functions from wider areas of the mouse cerebral cortex than those currently available with existing ECoG techniques.

neuroscience↗

bioRxiv2021

Myasthenia gravis-specific aberrant neuromuscular gene expression by medullary thymic epithelial cells in thymoma

Myasthenia gravis (MG) is a neurological disease caused by autoantibodies against neuromuscular-associated proteins. While MG is frequently developed in thymoma patients, the etiologic factors for MG are not well understood. Here, by constructing a comprehensive atlas of thymoma using bulk and single-cell RNA-seq, we identified ectopic expression of neuromuscular molecules in MG-associated thymoma (MG-thymoma). These molecules were originated from a distinct subpopulation of medullary thymic epithelial cells (mTECs), which we named neuromuscular mTECs (nmTECs). MG-thymoma also exhibited microenvironments dedicated to autoantibody production, including ectopic germinal center formation, T follicular helper cell accumulation, and type 2 conventional dendritic cell migration. Cell-cell interaction analysis also predicted the interaction between nmTECs and T/B cells via CXCL12-CXCR4. The enrichment of nmTECs presenting neuromuscular molecules within MG-thymoma was further confirmed by immunohistochemically and by cellular composition estimation from MG-thymoma transcriptome. Altogether, this study suggests that nmTECs play a significant role in MG pathogenesis via ectopic expression of neuromuscular molecules.

immunology↗

bioRxiv2020

Genetically-Modified Macrophages Accelerate Myelin Repair

Preventing neurodegeneration-associated disability progression in patients with multiple sclerosis (MS) remains an unmet therapeutic need. As remyelination prevents degeneration of demyelinated axons, promoting this process in patients might halt the development of permanent disability. In demyelinating mouse lesions, local overexpression of Semaphorin 3F (Sema3F), an oligodendrocyte progenitor cell (OPC) attractant, increases OPC recruitment and remyelination. However, molecular targeting to MS lesions is a challenge because these are disseminated in the central nervous system. We hypothesized that a clinically-relevant paradigm to deliver Sema3F to demyelinating lesions and increase OPC recruitment may be to use blood-derived macrophages as vehicles. Thus, we chose transplantation of genetically-modified hematopoietic stem cells (HSCs) as means of obtaining circulating monocytes that overexpress Sema3F. We first demonstrated that the supernatant from Sema3F-lentiviral vector transduced HSCs stimulates OPC migration in Neuropilin 2 (Nrp2, Sema3F receptor)-dependent fashion. We then investigated whether OPCs remain responsive to Sema3F with age. While Sema3F expression in the lesions of middle-aged and old mice (characterized by decreased efficiency of OPC recruitment and remyelination) was decreased, middle-aged OPCs retained Nrp2 expression and migrated in response to both recombinant Sema3F and Sema3F-transduced cell supernatant in vitro. We then investigated whether blood cells engineered to overexpress Sema3F can target demyelinating CNS lesions and improve remyelination. Thus, we transplanted Sema3F-transduced HSCs and obtained chimeric mice (with Sema3F overexpression in blood cells), in which we induced demyelinating spinal cord lesions. Transgene-carrying cells, predominantly macrophages, quickly infiltrated lesions in both control and Sema3F chimeras. While infiltration of Sema3F-expressing cells did not alter the inflammatory status of the lesions nor OPC survival, it increased OPC recruitment, which accelerated the onset of remyelination. Our results provide a proof-of-concept that blood cells, particularly monocyte-derived macrophages, can be used to deliver pro-remyelinating agents "at the right time and place", suggesting novel means for remyelination-promoting strategies.

neuroscience↗