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Cerebrospinal fluid draining lymphatics in health and disease: advances and controversies

Nature Cardiovascular Research volume 4, pages 1047–1065 (2025)Cite this article

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Abstract

The meninges, consisting of the dura, arachnoid and pia mater that surround the brain and spinal cord, have been recognized from the earliest anatomical studies. First identified in 1787, lymphatic vessels in the dura are now receiving greater attention as their contribution to cerebrospinal fluid (CSF) clearance in diverse neurological conditions is being investigated. New methods have increased the understanding of dural lymphatics, but much is still being learned about their heterogeneity, intracranial and extracranial connections, and factors that govern their functions and maintenance. Current research is striving to understand the regulation of CSF drainage and influence of brain antigen and immune cell transit through dural lymphatics on aging impairments and the severity of neurodegenerative and neuroimmune diseases, traumatic brain injury, stroke and other neurological disorders. Achieving these goals should lead to safe and effective methods for manipulating CSF clearance through dural lymphatics for therapeutic benefit.

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Fig. 1: Dural lymphatic involvement in neurological disorders and importance of CNS barriers.
Fig. 2: Evolving understanding of meningeal lymphatics.
Fig. 3: Lymphatic routes for CSF outflow and aging changes.

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Acknowledgements

This work was supported in part by funding from the National Heart, Lung, and Blood Institute grants (R01 HL143896, R01 HL059157 and R01 HL127402, to D.M.D.) from the US National Institutes of Health; Republic of Korea Ministry of Science and Information and Communication Technology to the Institute Basic Science (IBS-R025-D1-2015, to G.Y.K.); Wihuri Foundation, the European Union Horizon 2020 research and innovation program (874708, Theralymph), Sigrid Jusélius Foundation, Cancer Foundation Finland, and the Hospital District of Helsinki and Uusimaa (HUS Diagnostic Center, TYH2022202; to K.A.); Swedish Research Council (2015-00550, to C.B.); Swedish Cancer Society (2018/449, 2018/1154 and 211714Pj, to C.B.); Knut and Alice Wallenberg Foundation (2020.0057, to C.B.); Swedish Brain Foundation (ALZ2019-0130 and ALZ2022-0005, to C.B.); Erling-Persson Family Foundation (to C.B.); Leducq Foundation (22CVD01 and 23CVD02, to C.B.); Fidelity Bermuda Foundation (to S.P. and B.E.); Swiss National Science Foundation (310030_189080, to B.E.; 310030_189226 and 320030_231973, to S.P.; and CRSII5_213535, to S.P. and B.E.); and a National Institute of Neurological Disorders and Stroke grant (R01 NS098273, to J.S.) from the US National Institutes of Health.

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Author notes

  1. These authors contributed equally: Donald M. McDonald, Kari Alitalo, Christer Betsholtz, Britta Engelhardt, Steven T. Proulx, Julie Siegenthaler, Gou Young Koh.

Authors and Affiliations

  1. Department of Anatomy, Cardiovascular Research Institute, and UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA

    Donald M. McDonald

  2. Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki and Wihuri Research Institute, Helsinki, Finland

    Kari Alitalo

  3. Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden

    Christer Betsholtz

  4. Department of Medicine-Huddinge, Karolinska Institutet, Huddinge, Sweden

    Christer Betsholtz

  5. Theodor Kocher Institute, University of Bern, Bern, Switzerland

    Britta Engelhardt & Steven T. Proulx

  6. Department of Pediatrics, Section of Developmental Biology, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA

    Julie Siegenthaler

  7. Center for Vascular Research, Institute for Basic Science and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea

    Gou Young Koh

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McDonald, D.M., Alitalo, K., Betsholtz, C. et al. Cerebrospinal fluid draining lymphatics in health and disease: advances and controversies. Nat Cardiovasc Res 4, 1047–1065 (2025). https://doi.org/10.1038/s44161-025-00705-2

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