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Lithium Preconditioning Boosts Stroke Treatment by MSC-derived Extracellular Vesicles

Review of "Lithium modulates miR-1906 levels of MSC-derived extracellular vesicles contributing to post-stroke neuroprotection by toll-like receptor 4 regulation" from STEM CELLS Translational Medicine by Stuart P. Atkinson

While lithium has a well-recognized function as a mood stabilizer, a wide range of research now supports a neuroprotective role for lithium in conditions such as cerebral ischemia, traumatic brain injury, and neurodegeneration. Researchers led by Thorsten R. Doeppner (University Medical Center Göttingen, Germany) also demonstrated how lithium treatment promotes neuroprotection and neuroregeneration when applied within an early therapeutic time frame after experimental stroke [1].

In their new STEM CELLS Translational Medicine study [2], the authors explored the potential of lithium to improve the therapeutic potential of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs [3]) in stroke treatment, given encouraging studies that had previously assessed the transplantation of in vitro-preconditioned MSCs in experimental models of Huntington's disease and stroke [4, 5]. Using focal cerebral ischemia in a mouse model, Haupt et al. now report that treatment with EVs derived from lithium-preconditioned MSCs (Li-EVs) prompted neuroprotection and neuroregeneration following experimental stroke.

Initial in vitro evaluations established that treatment with Li-EVs provided astrocytes, microglia, and neurons with increased protection against the negative impact of hypoxic injury (associated with focal cerebral ischemia) when compared with EVs derived from un-preconditioned MSCs. Given these encouraging findings, the authors next moved in vivo to study the two EV populations in a mouse model of focal cerebral ischemia, which mimics human stroke. Interestingly, the intravenous delivery of Li-EVs prompted an increase in neurological recovery and neuroregeneration over three months; however, Li-EVs and EVs derived from un-preconditioned MSCs both afforded significantly better behavioral improvements when compared to control untreated mice.

Analysis of EVs to decipher how lithium had provided them with an increased therapeutic potential revealed the altered expression of distinct microRNAs species. Specifically, Li-EVs displayed an enrichment for miR‐1906, which regulates toll‐like receptor 4 (TLR4) signaling [6]. In agreement with this finding, treatment with Li-EVs prompted a reduction in TLR4 abundance after hypoxia in vitro and ischemia in vivo. This alteration then reduced pro-inflammatory nuclear factor kappa B (NF‐κB) signaling, proteasomal activity, and nitric oxide synthase and cyclooxygenase‐2 expression, which induced an overall reduction in the levels of post-stroke cerebral inflammation and an increase in neurological recovery.

Overall, these findings suggest that lithium preconditioning leads to the generation of MSC-derived EVs with increased neuroprotective and neuroregenerative abilities, thereby providing proof-of-concept for subsequent translational studies and clinical trials for stroke.

For more on stem cell preconditioning, extracellular vesicles, and the development of novel therapeutics for stroke, stay tuned to the Stem Cells Portal!


References

  1. Doeppner TR, Kaltwasser B, Sanchez-Mendoza EH, et al., Lithium-induced neuroprotection in stroke involves increased miR-124 expression, reduced RE1-silencing transcription factor abundance and decreased protein deubiquitination by GSK3β inhibition-independent pathways. Journal of Cerebral Blood Flow & Metabolism 2016;37:914-926.
  2. Haupt M, Zheng X, Kuang Y, et al., Lithium modulates miR-1906 levels of mesenchymal stem cell-derived extracellular vesicles contributing to poststroke neuroprotection by toll-like receptor 4 regulation. STEM CELLS Translational Medicine 2021;10:357-373.
  3. Théry C, Witwer KW, Aikawa E, et al., Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. Journal of Extracellular Vesicles 2018;7:1535750.
  4. Linares GR, Chiu C-T, Scheuing L, et al., Preconditioning mesenchymal stem cells with the mood stabilizers lithium and valproic acid enhances therapeutic efficacy in a mouse model of Huntington's disease. Experimental Neurology 2016;281:81-92.
  5. Tsai L-K, Wang Z, Munasinghe J, et al., Mesenchymal Stem Cells Primed With Valproate and Lithium Robustly Migrate to Infarcted Regions and Facilitate Recovery in a Stroke Model. Stroke 2011;42:2932-2939.
  6. Xu X, Wen Z, Zhao N, et al., MicroRNA-1906, a Novel Regulator of Toll-Like Receptor 4, Ameliorates Ischemic Injury after Experimental Stroke in Mice. The Journal of Neuroscience 2017;37:10498.