Increased CSF drainage by non-invasive manipulation of cervical lymphatics

• 成果类型: Article
• 署名作者: Jin, Hokyung; Yoon, Jin-Hui; Hong, Seon Pyo; Hwang, Yu Seok; Yang, Myung Jin; Choi, Jieun; Kang, Hae Jin; Baek, Seung Eun; Jin, Cheolhwa; Jung, Junho; Kim, Hae Jin; Seo, Jincheol; Won, Jinyoung; Lim, Kyung Seob; Jeon, Chang-Yeop; Lee, Youngjeon; Davis, Michael J.; Park, Hyung-Soon; Mcdonald, Donald M.; Koh, Gou Young
• 署名单位: Institute for Basic Science - Korea (IBS); Korea Advanced Institute of Science & Technology (KAIST); Korea Advanced Institute of Science & Technology (KAIST); University of Missouri System; University of Missouri Columbia; Korea Research Institute of Bioscience & Biotechnology (KRIBB); Korea Research Institute of Bioscience & Biotechnology (KRIBB); University of Science & Technology (UST); University of California System; University of California San Francisco; University of California System; University of California San Francisco; UCSF Medical Center; UCSF Helen Diller Family Comprehensive Cancer Center
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1060
• DOI: 10.1038/s41586-025-09052-5
• 发表日期: 2025-07-17
• 关键词: cerebrospinal-fluid; subarachnoid injection; nasal lymphatics; rat; connections; transport; vessels; SYSTEM; SPACE; blood

摘要

Cerebrospinal fluid (CSF) in the subarachnoid space around the brain drains to lymph nodes in the neck, but the connections and regulation have been challenging to identify1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23-24. Here we used fluorescent tracers in Prox1-GFP lymphatic reporter mice to map the pathway of CSF outflow through lymphatics to superficial cervical lymph nodes. CSF entered initial lymphatics in the meninges at the skull base and continued through extracranial periorbital, olfactory, nasopharyngeal and hard palate lymphatics, and then through smooth muscle-covered superficial cervical lymphatics to submandibular lymph nodes. Tracer studies in adult mice revealed that a substantial amount of total CSF outflow to the neck drained to superficial cervical lymph nodes. However, aged mice had fewer lymphatics in the nasal mucosa and hard palate and reduced CSF outflow to cervical lymph nodes. Superficial cervical lymphatics in aged mice had increased endothelial cell expression of Nos3, encoding endothelial nitric oxide synthase (eNOS), but had less eNOS protein and impaired nitric oxide signalling. Manipulation of superficial cervical lymphatics through intact skin by a force-regulated mechanical device doubled CSF outflow and corrected drainage impairment in aged mice. This manipulation increased CSF outflow by compressing superficial cervical lymphatics while having little effect on their normal spontaneous contractions. Overall, the findings highlight the importance of superficial cervical lymphatics for CSF outflow and the potential for reversing CSF drainage impairment by non-invasive mechanical stimulation.