Int J Biol Sci 2022; 18(14):5345-5368. doi:10.7150/ijbs.73747 This issue

Research Paper

Mesenchymal stromal cell-derived extracellular vesicles afford neuroprotection by modulating PI3K/AKT pathway and calcium oscillations

Egor A. Turovsky1, Victoria V. Golovicheva2, Elena G. Varlamova1, Tatyana I. Danilina2, Kirill V. Goryunov4, Yulia A. Shevtsova4,5, Irina B. Pevzner2,4, Ljubava D. Zorova2,4, Valentina A. Babenko2,4, Ekaterina A. Evtushenko3, Anastasia A. Zharikova5, Anastasia A. Khutornenko4, Sergey I. Kovalchuk6, Egor Y. Plotnikov2,4, Dmitry B. Zorov2,4✉, Gennady T. Sukhikh4, Denis N. Silachev2,4✉

1. Institute of Cell Biophysics of the Russian Academy of Sciences, Federal Research Center “Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences”, 142290 Pushchino, Russia.
2. A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia.
3. Faculty of Biology, Lomonosov Moscow State University, Moscow 119234, Russia.
4. V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 117997 Moscow, Russia.
5. Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119234 Moscow, Russia.
6. Laboratory of Bioinformatics Methods in Combinatorial Chemistry and Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences; 117997 Moscow, Russia.

This is an open access article distributed under the terms of the Creative Commons Attribution License ( See for full terms and conditions.
Turovsky EA, Golovicheva VV, Varlamova EG, Danilina TI, Goryunov KV, Shevtsova YA, Pevzner IB, Zorova LD, Babenko VA, Evtushenko EA, Zharikova AA, Khutornenko AA, Kovalchuk SI, Plotnikov EY, Zorov DB, Sukhikh GT, Silachev DN. Mesenchymal stromal cell-derived extracellular vesicles afford neuroprotection by modulating PI3K/AKT pathway and calcium oscillations. Int J Biol Sci 2022; 18(14):5345-5368. doi:10.7150/ijbs.73747. Available from

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Graphic abstract

Mesenchymal stromal cells (MSC) are widely recognized as potential effectors in neuroprotective therapy. The protective properties of MSC were considered to be associated with the secretion of extracellular vesicles (MSC-EV). We explored the effects of MSC-EV in vivo on models of traumatic and hypoxia-ischemia (HI) brain injury. Neuroprotective mechanisms triggered by MSC-EV were also studied in vitro using a primary neuroglial culture. Intranasal administration of MSC-EV reduced the volume of traumatic brain damage, correlating with a recovery of sensorimotor functions. Neonatal HI-induced brain damage was mitigated by the MSC-EV administration. This therapy also promoted the recovery of sensorimotor functions, implying enhanced neuroplasticity, and MSC-EV-induced growth of neurites in vitro supports this. In the in vitro ischemic model, MSC-EV prevented cell calcium (Ca2+) overload and subsequent cell death. In mixed neuroglial culture, MSC-EV induced inositol trisphosphate (IP3) receptor-related Ca2+ oscillations in astrocytes were associated with resistance to calcium overload not only in astrocytes but also in co-cultured neurons, demonstrating intercellular positive crosstalk between neural cells. This implies that phosphatidylinositol 3-Kinase/AKT signaling is one of the main pathways in MSC-EV-mediated protection of neural cells exposed to ischemic challenge. Components of this pathway were identified among the most enriched categories in the MSC-EV proteome.

Keywords: Multipotent mesenchymal stromal cells, extracellular vesicles, neuroprotection, neonatal hypoxic-ischemic encephalopathy, traumatic brain injury, calcium oscillations, the phosphatidylinositol 3‑kinase (PI3K)/protein kinase B (AKT) signaling pathway