Age-related meningeal extracellular matrix remodeling compromises CNS lymphatic function

Area of Science:

• Neuroscience
• Immunology
• Vascular Biology

Background:

• Efficient clearance of central nervous system (CNS) waste and immune surveillance are vital for brain health.
• Meningeal lymphatic networks facilitate cerebrospinal fluid (CSF) drainage, but age-related impairments are poorly understood.
• These impairments contribute to CNS waste accumulation and immune dysfunction.

Purpose of the Study:

• To identify mechanisms underlying age-related deficits in meningeal lymphatic drainage.
• To investigate the role of extracellular matrix (ECM) remodeling in the aged dura mater.
• To explore immune-derived factors regulating ECM remodeling and lymphatic function.

Main Methods:

• Analysis of ECM remodeling in the aged dura.
• Identification of transforming growth factor beta 1 (TGFβ1) as a regulator using primary human dural fibroblasts.
• Utilizing a novel mouse model with constitutively active TGFβ receptor 1 (TGFβR1) signaling in dural fibroblasts.
• Investigating the impact of ECM stiffness on lymphatic endothelial cells.

Main Results:

• Extracellular matrix (ECM) remodeling, specifically collagen accumulation in the aged dura, disrupts meningeal lymphatic drainage.
• Transforming growth factor beta 1 (TGFβ1) significantly contributes to ECM remodeling.
• Constitutively active TGFβR1 signaling in dural fibroblasts leads to impaired lymphatic drainage and altered meningeal immunity.
• Increased ECM stiffness disrupts lymphatic junction integrity and lymphangiogenesis.

Conclusions:

• Dural immune cell and fibroblast-mediated ECM remodeling is a critical regulator of CSF clearance.
• Age-related ECM changes impair meningeal lymphatic function, contributing to brain waste accumulation.
• Targeting ECM remodeling presents a potential therapeutic strategy for restoring brain waste clearance in aging.