Open AccessLithium modulates miR ‐1906 levels of mesenchymal stem cell‐derived extracellular vesicles contributing to poststroke neuroprotection by toll‐like receptor 4 regulation
Author(s) -
Haupt Matteo,
Zheng Xuan,
Kuang Yaoyun,
Lieschke Simone,
Janssen Lisa,
Bosche Bert,
Jin Fengyan,
Hein Katharina,
Kilic Ertugrul,
Venkataramani Vivek,
Hermann Dirk M.,
Bähr Mathias,
Doeppner Thorsten R.
Publication year - 2021
Publication title -
stem cells translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.781
H-Index - 71
eISSN - 2157-6580
pISSN - 2157-6564
DOI - 10.1002/sctm.20-0086
Subject(s) - neuroregeneration , neuroprotection , mesenchymal stem cell , extracellular vesicle , microglia , tlr4 , neurogenesis , microbiology and biotechnology , pharmacology , inflammation , medicine , microvesicles , chemistry , immunology , biology , microrna , biochemistry , gene
Lithium is neuroprotective in preclinical stroke models. In addition to that, poststroke neuroregeneration is stimulated upon transplantation of mesenchymal stem cells (MSCs). Preconditioning of MSCs with lithium further enhances the neuroregenerative potential of MSCs, which act by secreting extracellular vesicles (EVs). The present work analyzed whether MSC preconditioning with lithium modifies EV secretion patterns, enhancing the therapeutic potential of such derived EVs (Li‐EVs) in comparison with EVs enriched from native MSCs. Indeed, Li‐EVs significantly enhanced the resistance of cultured astrocytes, microglia, and neurons against hypoxic injury when compared with controls and to native EV‐treated cells. Using a stroke mouse model, intravenous delivery of Li‐EVs increased neurological recovery and neuroregeneration for as long as 3 months in comparison with controls and EV‐treated mice, albeit the latter also showed significantly better behavioral test performance compared with controls. Preconditioning of MSCs with lithium also changed the secretion patterns for such EVs, modifying the contents of various miRNAs within these vesicles. As such, Li‐EVs displayed significantly increased levels of miR‐1906, which has been shown to be a new regulator of toll‐like receptor 4 (TLR4) signaling. Li‐EVs reduced posthypoxic and postischemic TLR4 abundance, resulting in an inhibition of the nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) signaling pathway, decreased proteasomal activity, and declined both inducible NO synthase and cyclooxygenase‐2 expression, all of which culminated in reduced levels of poststroke cerebral inflammation. Conclusively, the present study demonstrates, for the first time, an enhanced therapeutic potential of Li‐EVs compared with native EVs, interfering with a novel signaling pathway that yields both acute neuroprotection and enhanced neurological recovery.