Mesenchymal Stromal Cells Play an Analgesic Role Through a <i>Npy2r</i> Sensory Neuron‐Mediated Lung‐to‐Brain Axis
Mesenchymal stromal cells (MSC) have emerged as a promising therapeutic option for neuropathic pain (NP), but the mechanisms remain elusive. Using murine pain models, it is demonstrated that MSC effectively alleviates pain, with efficacy comparable to dexmedetomidine, a moderate analgesic. Mechanistically, peripheral delivery of MSC-activated pulmonary Npy2r-expressing vagal sensory neurons, which project to the nucleus tractus solitarius and ventral lateral periaqueductal gray area, drives analgesia via the vagal lung-to-brain pathway. Chemogenetic activation of Npy2r sensory neurons similarly ameliorates spared nerve injury (SNI)-induced mechanical allodynia and thermal hyperalgesia. Furthermore, it is found that MSC-derived extracellular ATP, released via pannexin1, activates Npy2r sensory neurons through purinergic receptor P2X2 (P2rx2). Strikingly, inhalation of a P2rx2 agonist produced significant therapeutic effects in SNI mice. Together, these findings reveal that Npy2r sensory neuron-mediated lung-brain axis underlies MSC-induced analgesia and highlight the potential of targeting body-brain pathways for novel NP treatments.
Authors
- Yiwen Deng (ORCID: https://orcid.org/0000-0002-6074-5704)
- Xiaoran Zhang (ORCID: https://orcid.org/0000-0001-6421-0355)
- Andy Peng Xiang (ORCID: https://orcid.org/0000-0003-3409-5012)
- Yunli Tong (ORCID: https://orcid.org/0009-0001-3743-3403)
- Rui Fang (ORCID: https://orcid.org/0009-0009-7249-3012)
- Xia Feng (ORCID: https://orcid.org/0000-0001-8182-9803)
- Xu‐Hong Wei (ORCID: https://orcid.org/0000-0002-9722-3694)
- Heshe Li
- Zheming Liu (ORCID: https://orcid.org/0000-0001-5610-6558)
- Xiaoting Tu
- Lu Zhu (ORCID: https://orcid.org/0000-0003-2716-4649)
- Ying Wang (ORCID: https://orcid.org/0000-0002-0591-662X)
- Tao Wang (ORCID: https://orcid.org/0000-0002-8955-416X)
- Jianqi Feng
- Ruijie Li (ORCID: https://orcid.org/0000-0001-8219-1733)
- Xiaoyong Chen (ORCID: https://orcid.org/0000-0003-4205-3613)
- Yueming Sun (ORCID: https://orcid.org/0000-0003-4448-4046)
- Li Huang (ORCID: https://orcid.org/0000-0002-5964-7090)
- Keyu Chen (ORCID: https://orcid.org/0000-0003-0321-0604)
- Yuanchen Ma (ORCID: https://orcid.org/0000-0003-0490-3744)
- Yuantao Li (ORCID: https://orcid.org/0000-0003-4531-7864)
- Yuan Qiu (ORCID: https://orcid.org/0000-0001-7104-616X)
- Lin Nie (ORCID: https://orcid.org/0009-0008-7788-4576)
- Jing Huang (ORCID: https://orcid.org/0000-0003-2535-7308)
- Robert Lin
- Taihe Zhou
Institutions
- Jiujiang University (CN)
- Sun Yat-sen University (CN)
- Guangzhou Development Zone Hospital (CN)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
- Gaozhou People's Hospital (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-08-28
- DOI
- https://doi.org/10.1002/advs.202504922
- Primary Topic
- Biochemical Analysis and Sensing Techniques
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- China Association for Science and Technology
- National Natural Science Foundation of China
- Natural Science Foundation of Guangdong Province
- National Key Research and Development Program of China
- National Key Research and Development Program of China Stem Cell and Translational Research