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Background <p>The ependymal glycocalyx (Gcx) is a glycan-rich apical structure that lines the ventricular brain surface. It is thought to contribute to cerebrospinal fluid dynamics and brain homeostasis by forming a selective barrier, preserving surface charge, and supporting ciliary function. Despite its importance, the structural integrity and glycan composition of the ependymal Gcx remain poorly understood, particularly in the context of physiological aging and acute neurological injury, such as intraventricular hemorrhage (IVH). We aimed to elucidate the physiological role of the ependymal Gcx and its alterations in response to aging and acute brain injury.</p> Methods <p>We comprehensively investigated age- and injury-related changes in the ependymal Gcx using young (8–10-week-old), aged (60–62-week-old), and IVH model mice. The Gcx structure was visualized using lanthanum-enhanced electron microscopy, and glycan profiles were assessed through double immunofluorescence staining with S100β and a panel of 21 fluorescent lectins. Gcx thickness was quantitatively analyzed using a novel image analysis approach based on fluorescence intensity profiles. Single-cell RNA sequencing (scRNA-seq) was performed on ventricular tissue to identify transcriptional changes in aged ependymal cells related to glycan biosynthesis, glycan sialylation, desialylation, vesicular transport, and inflammatory responses.</p> Results <p>Immunohistochemistry showed that, in young mice, the ependymal Gcx was bound to SiaFind and Lycopersicon esculentum lectin; additionally, it is bound to PNA even without desialylation. In aged mice, the Gcx displayed marked thinning, detachment, and significant loss of terminal sialic acids. In young mice, Gcx disruption after IVH peaked on day 3 and correlated with periventricular inflammation; in contrast, the inflammation persisted in aged IVH mice. Integrated single-cell RNA-seq revealed age-related alterations. Key sialylation genes (ST3GAL1, SLC35A1) and core 1 O-glycan enzymes (C1GALT1, C1GALT1C1) were downregulated, whereas ST3GAL5 and plasma-membrane sialidase NEU3 were upregulated. Additionally, senescence markers (Cdkn1a, Trp53) and multiple interferon-stimulated genes were elevated.</p> Conclusions <p>The ependymal Gcx is a dynamic and injury-sensitive structure whose integrity is compromised by aging and IVH. Its disruption promotes neuroinflammation and may contribute to the development of hydrocephalus and neurodegeneration. Therapeutic modulation of glycosylation pathways may provide a promising strategy to preserve Gcx function and protect the internal brain environment.</p>

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Age‑dependent and post‑intraventricular hemorrhage remodeling of the ependymal glycocalyx in mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月7日

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  • Tomohiro Iida,
  • Kosuke Mori,
  • Hiroyuki Tomita,
  • Kazufumi Ohmura,
  • Kohtaro Taguchi,
  • Ayumi Niwa,
  • Tomohiro Kanayama,
  • Shigeyuki Sugie,
  • Hideshi Okada,
  • Tsuyoshi Izumo,
  • Akira Hara

摘要

Background

The ependymal glycocalyx (Gcx) is a glycan-rich apical structure that lines the ventricular brain surface. It is thought to contribute to cerebrospinal fluid dynamics and brain homeostasis by forming a selective barrier, preserving surface charge, and supporting ciliary function. Despite its importance, the structural integrity and glycan composition of the ependymal Gcx remain poorly understood, particularly in the context of physiological aging and acute neurological injury, such as intraventricular hemorrhage (IVH). We aimed to elucidate the physiological role of the ependymal Gcx and its alterations in response to aging and acute brain injury.

Methods

We comprehensively investigated age- and injury-related changes in the ependymal Gcx using young (8–10-week-old), aged (60–62-week-old), and IVH model mice. The Gcx structure was visualized using lanthanum-enhanced electron microscopy, and glycan profiles were assessed through double immunofluorescence staining with S100β and a panel of 21 fluorescent lectins. Gcx thickness was quantitatively analyzed using a novel image analysis approach based on fluorescence intensity profiles. Single-cell RNA sequencing (scRNA-seq) was performed on ventricular tissue to identify transcriptional changes in aged ependymal cells related to glycan biosynthesis, glycan sialylation, desialylation, vesicular transport, and inflammatory responses.

Results

Immunohistochemistry showed that, in young mice, the ependymal Gcx was bound to SiaFind and Lycopersicon esculentum lectin; additionally, it is bound to PNA even without desialylation. In aged mice, the Gcx displayed marked thinning, detachment, and significant loss of terminal sialic acids. In young mice, Gcx disruption after IVH peaked on day 3 and correlated with periventricular inflammation; in contrast, the inflammation persisted in aged IVH mice. Integrated single-cell RNA-seq revealed age-related alterations. Key sialylation genes (ST3GAL1, SLC35A1) and core 1 O-glycan enzymes (C1GALT1, C1GALT1C1) were downregulated, whereas ST3GAL5 and plasma-membrane sialidase NEU3 were upregulated. Additionally, senescence markers (Cdkn1a, Trp53) and multiple interferon-stimulated genes were elevated.

Conclusions

The ependymal Gcx is a dynamic and injury-sensitive structure whose integrity is compromised by aging and IVH. Its disruption promotes neuroinflammation and may contribute to the development of hydrocephalus and neurodegeneration. Therapeutic modulation of glycosylation pathways may provide a promising strategy to preserve Gcx function and protect the internal brain environment.