Umbilical Cord Mesenchymal Stromal Cell-Derived Extracellular Vesicles Transfer CD59 to Astrocytes to Alleviate Complement-Dependent Cytotoxicity

  • Mol Neurobiol. 2025 Nov 14;63(1):41. doi: 10.1007/s12035-025-05298-2.
Qi Shen  #  1 ,  Xueying Wang  #  1 ,  Qingjian Ou  #  1 ,  Qian Wang  1 ,  Zhenzhen Zhao  1 ,  Zhiyang Chen  1 ,  Xiaoman Zhu  1 ,  Dongli Li  1 ,  Caixia Jin  1 ,  Furong Gao  1 ,  Juan Wang  1 ,  Lixia Lu  1 ,  Yanlong Bi  1 ,  Wenbin Wan  2 ,  Yangtai Guan  2 ,  Guo-Tong Xu  #  3  4 ,  Jing-Ying Xu  #  5 ,  Haibin Tian  #  6  7
Affiliations
  • 1. Department of Ophthalmology of Tongji Hospital and Laboratory of Clinical and Visual Sciences of Tongji Eye Institute, School of Medicine, Tongji University, Shanghai, 200065, China.
  • 2. Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
  • 3. Department of Ophthalmology of Tongji Hospital and Laboratory of Clinical and Visual Sciences of Tongji Eye Institute, School of Medicine, Tongji University, Shanghai, 200065, China. [email protected].
  • 4. The Collaborative Innovation Center for Brain Science, Tongji University, Shanghai, 200092, China. [email protected].
  • 5. Department of Ophthalmology of Tongji Hospital and Laboratory of Clinical and Visual Sciences of Tongji Eye Institute, School of Medicine, Tongji University, Shanghai, 200065, China. [email protected].
  • 6. Department of Ophthalmology of Tongji Hospital and Laboratory of Clinical and Visual Sciences of Tongji Eye Institute, School of Medicine, Tongji University, Shanghai, 200065, China. [email protected].
  • 7. Department of Pharmacology, School of Medicine, Tongji University, Shanghai, 200092, China. [email protected].
  • # Contributed equally.
PMID: 41236660 DOI: 10.1007/s12035-025-05298-2
Abstract

The retinal astrocyte death induced by complement-dependent cytotoxicity (CDC) is the major etiology of retinal injury in patients with neuromyelitis optica spectrum disorders (NMOSD). Human umbilical cord-derived mesenchymal stromal cells (hUCMSCs) and their derived extracellular vesicles (EVs) have emerged as a potential therapeutic option due to their immunomodulatory capabilities. This study is aimed at establishing a serum-free culture system for hUCMSCs (SF-UCMSCs) and investigating the inhibiting effect of EVs derived from SF-UCMSCs on CDC-induced retinal astrocyte death. The results showed that SF-UCMSCs retained canonical mesenchymal stromal cells' characteristics under serum-free culture conditions. Pharmacokinetic analysis showed that intravenously administered SF-UCMSCs predominantly accumulated in the lungs, liver, spleen, and kidneys, with no detectable localization in the retina. Notably, EVs derived from SF-UCMSCs exerted a protective effect against CDC-mediated damage to murine retinal astrocytes, as evidenced by reduced formation of C5b-9 + membrane attack complexes and diminished astrocyte death. Mechanistically, this protective effect was associated with the transfer of CD59 from EVs to astrocytes. In summary, the establishment of this serum-free culture system facilitates the development of hUCMSC-derived EVs as therapeutic agents, circumventing the risks of immune rejection and potential tumorigenicity associated with cellular transplantation. This study also provides a mechanistic basis and therapeutic strategy for managing autoimmune diseases characterized by CDC-mediated pathogenesis.

Keywords
Astrocyte; CD59; Complement-dependent cytotoxicity; Extracellular vesicle; Human umbilical cord-derived mesenchymal stromal cells.
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