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<p>Efficient clearance of central nervous system (CNS) waste proteins and appropriate immune surveillance is essential for brain health. These processes are facilitated by lymphatic networks present in the meninges that drain cerebrospinal fluid (CSF). Age-related impairments to meningeal lymphatic drainage contribute to CNS waste accumulation and immune dysfunction, yet the underlying mechanisms remain poorly understood. Here, we identify extracellular matrix (ECM) remodeling in the aged dura as a key driver of CSF clearance deficits, demonstrating that peri-lymphatic collagen accumulation disrupts lymphatic function. Exploring immune-derived factors contributing to this ECM remodeling, we identify transforming growth factor beta 1 (TGFβ1) as a major regulator using primary human dural fibroblasts. Using a novel mouse model with constitutively active TGFβ receptor 1 (TGFβR1) signaling in dural fibroblasts, we show that excessive peri-lymphatic collagen deposition impairs meningeal lymphatic drainage and alters meningeal immunity. Mechanistically, we reveal that ECM-associated matrix stiffness disrupts lymphatic junction integrity and impairs lymphangiogenesis in human lymphatic endothelial cells. These findings establish dural immune cell and fibroblast-mediated ECM remodeling as a critical regulator of CSF clearance and highlight it as a potential therapeutic target for restoring brain waste clearance in aging.</p>

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Age-related meningeal extracellular matrix remodeling compromises CNS lymphatic function

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年4月17日

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  • Kate Hitpass Romero,
  • Taylor J. Stevenson,
  • Leon C. D. Smyth,
  • Ben Watkin,
  • Samuel J.C. McCullough,
  • Luca Vinnell,
  • Amy M. Smith,
  • Patrick Schweder,
  • Jason A. Correia,
  • Jonathan Kipnis,
  • Mike Dragunow,
  • Justin Rustenhoven

摘要

Efficient clearance of central nervous system (CNS) waste proteins and appropriate immune surveillance is essential for brain health. These processes are facilitated by lymphatic networks present in the meninges that drain cerebrospinal fluid (CSF). Age-related impairments to meningeal lymphatic drainage contribute to CNS waste accumulation and immune dysfunction, yet the underlying mechanisms remain poorly understood. Here, we identify extracellular matrix (ECM) remodeling in the aged dura as a key driver of CSF clearance deficits, demonstrating that peri-lymphatic collagen accumulation disrupts lymphatic function. Exploring immune-derived factors contributing to this ECM remodeling, we identify transforming growth factor beta 1 (TGFβ1) as a major regulator using primary human dural fibroblasts. Using a novel mouse model with constitutively active TGFβ receptor 1 (TGFβR1) signaling in dural fibroblasts, we show that excessive peri-lymphatic collagen deposition impairs meningeal lymphatic drainage and alters meningeal immunity. Mechanistically, we reveal that ECM-associated matrix stiffness disrupts lymphatic junction integrity and impairs lymphangiogenesis in human lymphatic endothelial cells. These findings establish dural immune cell and fibroblast-mediated ECM remodeling as a critical regulator of CSF clearance and highlight it as a potential therapeutic target for restoring brain waste clearance in aging.