Mesenchymal Stromal Cells Play an Analgesic Role Through a Npy2r Sensory Neuron-Mediated Lung-to-Brain Axis

  • Adv Sci (Weinh). 2025 Aug 28:e04922. doi: 10.1002/advs.202504922.
Jing Huang  1  2  3 ,  Taihe Zhou  4 ,  Yueming Sun  2  3 ,  Yuanchen Ma  2  3 ,  Yiwen Deng  5 ,  Keyu Chen  1 ,  Ruijie Li  2  3 ,  Yuan Qiu  2  3 ,  Tao Wang  2  3 ,  Xiaoyong Chen  2  3 ,  Li Huang  6 ,  Lu Zhu  2  3 ,  Xueyi Tu  2  3 ,  Ying Wang  2  3 ,  Zheming Liu  2  3 ,  Rouchen Lin  2  3 ,  Yunli Tong  2  3 ,  Yuantao Li  2  3 ,  Heshe Li  2  3 ,  Lin Nie  2  3 ,  Rui Fang  7 ,  Jianqi Feng  7 ,  Xuhong Wei  4 ,  Xia Feng  1 ,  Andy Peng Xiang  1  2  3  8 ,  Xiaoran Zhang  1  2  3  8
Affiliations
  • 1. Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
  • 2. Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China.
  • 3. National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China.
  • 4. Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China.
  • 5. Jiangxi Provincial Key Laboratory of Cell Precision Therapy, School of Basic Medical Sciences, Jiujiang University, Jiujiang, Jiangxi, 332005, China.
  • 6. Center of Stem Cell and Regenerative Medicine, Gaozhou People's Hospital, Maoming, Guangdong, 525000, China.
  • 7. Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen, China.
  • 8. Department of Histoembryology and Cell Biology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China.
PMID: 40874463 DOI: 10.1002/advs.202504922
Abstract

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.

Keywords
Npy2r sensory neuron; analgesia; mesenchymal stem/stromal cells (MSC); vagal lung‐to‐brain axis.
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