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

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 (Ca 2+ ) overload and subsequent cell death. In mixed neuroglial culture, MSC-EV induced inositol trisphosphate (IP3) receptor-related Ca 2+ 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.

A Comparative Study of Mesenchymal Stem Cell-Derived Extracellular Vesicles’ Local and Systemic Dose-Dependent Administration in Rat Spinal Cord Injury

“…In other experimental groups, the level of C3 and S100a10 gene mRNA expression was higher and had no significant difference from the SCI control group after the transplantation of high doses of MSC-EVs. It was shown that the addition of MSC-EVs to the neuroglia culture can influence/modulate intracellular calcium fluxes in astrocytes but not in neurons [ 23 ]. There are many data showing the participation of calcium ions in hereditary and acquired neuropathogenesis.…”

“…In addition, MSC-derived EVs have been shown to be able to modulate microglia towards the neuroprotective M2 phenotype and reduce neuroinflammation [ 22 ]. Another study [ 23 ] investigated the Ca 2+ ion-associated intracellular mechanism by examining the neuroprotective effects of MSC-EVs when administered intranasally in two in vivo models of acute brain injury. The authors showed that by activating the PI3K signaling pathway and preventing calcium overload, MSC-EVs protected astrocytes and neurons from cell death under ischemia-like conditions.…”

The Role of Extracellular Vesicles in Ischemic Stroke Severity

“…Furthermore, the modalities and outcomes of the interaction between the different EV subtypes and the target cells during hypoxic damage are yet to be thoroughly investigated in order to clarify their role and to identify possible new therapeutic approaches. As a matter of fact, EVs contain a wide range of bioactive molecules that can mediate neuroprotection through several mechanisms of action (e.g., antiapoptotic and antioxidative signaling pathways) [ 1 , 33 ].…”

Therapeutic Potential of Extracellular Vesicles in Aging and Age-Related Diseases

“…Nervous tissue has a limited regenerative capacity upon several types of damage, both in peripheral nervous tissue and in the central nervous system [ 82 ]. Stem cell-derived EVs have been shown to improve regeneration of the nervous tissue after some types of damage in several animal models, such as peripheral nerve denervation [ 83 , 84 ], trauma [ 85 ], and stroke [ 86 , 87 ], with a neuroprotective effect on models of hypoxic-ischemic encephalopathy [ 69 , 88 ]. These EVs seem to exert this role through different processes and pathways associated with nerve regeneration.…”

“…These EVs seem to exert this role through different processes and pathways associated with nerve regeneration. For example, in a recent study, Turovsky et al demonstrated that EVs from MSCs exert a neuroprotective effect in a mouse model of ischemia through the modulation of phosphatidylinositol 3-Kinase/AKT signaling and calcium oscillations [ 69 ]. Moreover, EVs from different sources can induce changes in the glial cells, increasing the percentage of proliferating Schwann cells by 20% and increasing the myelinating potential of oligodendrocytes [ 89 ].…”