通过对颈部淋巴管进行非侵入性操作增加脑脊液引流。
Increased CSF drainage by non-invasive manipulation of cervical lymphatics.
作者信息
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
机构信息
Center for Vascular Research, Institute for Basic Science, Daejeon, Republic of Korea.
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
出版信息
Nature. 2025 Jun 4. doi: 10.1038/s41586-025-09052-5.
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 identify. 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.
脑周围蛛网膜下腔中的脑脊液(CSF)引流至颈部淋巴结,但其间的连接和调节机制一直难以确定。在此,我们在Prox1-GFP淋巴报告基因小鼠中使用荧光示踪剂,绘制脑脊液通过淋巴管流向颈浅淋巴结的流出路径。脑脊液在颅底脑膜处进入初始淋巴管,然后通过颅外眶周、嗅觉、鼻咽和硬腭淋巴管,再通过平滑肌覆盖的颈浅淋巴管流向颌下淋巴结。对成年小鼠的示踪研究表明,流向颈部的脑脊液总量中有相当一部分引流至颈浅淋巴结。然而,老年小鼠鼻黏膜和硬腭中的淋巴管较少,脑脊液向颈淋巴结的流出减少。老年小鼠的颈浅淋巴管中编码内皮型一氧化氮合酶(eNOS)的Nos3的内皮细胞表达增加,但eNOS蛋白较少,一氧化氮信号传导受损。通过一种力调节机械装置经完整皮肤对颈浅淋巴管进行操作,可使老年小鼠的脑脊液流出量增加一倍,并纠正引流障碍。这种操作通过压缩颈浅淋巴管增加了脑脊液流出量,同时对其正常的自发收缩影响很小。总体而言,这些发现突出了颈浅淋巴管对脑脊液流出的重要性,以及通过非侵入性机械刺激逆转脑脊液引流障碍的潜力。