Astrocytes are the most abundant type of glial cells, and studies have reported that astrocyte-derived EVs (ADEVs) are key players in glia-neuron communication. They have been found to contribute to neuron maturation and the survival and modulation of synaptic function (Durkee and Araque, 2019). ADEVs vary in size ranging from 150 to 500 nm and carry various transfer molecules, including ATP, Hsp/Hsc70, and synapsin I and angiogenesis modulating factors, such as fibroblast growth factor 2 (FGF2), vascular endothelial growth factor (VEGF), pigment epithelium-derived factor (PEDF), and endostatin (Proia et al., 2008; Pegtel et al., 2010; Frühbeis et al., 2013b; Agnati and Fuxe, 2014). Studies have shown that ADEVs also transport mitochondrial DNA (Guescini et al., 2010) and microRNA (miRNA), which contribute to intercellular communication (Jovičić and Gitler, 2017). The neuroprotecting properties of ADEVs have been shown to be effective against hypoxia, ischemia, oxidative stress, and hypoglycemia through prion protein-dependent mechanisms (Guitart et al., 2016; Pascua-Maestro et al., 2019). Reduced neuronal cell death has been reported through the exposure of ADEVs to oxygen and glucose deprivation (Xu et al., 2019). Regulation of autophagy by ADEVs has demonstrated apoptosis inhibition in neurons (Pei et al., 2019). Moreover, the role of ADEVs in traumatic brain injuries was recently shown to contribute to neuroprotection and damage repair through mitochondrial function, restoration, and apoptosis downregulation (Chen et al., 2020).

Neuronal morphology, dendritic development, and synaptic homeostasis have been proven to be directly regulated by ADEVs through modification of their miRNA cargo (Chaudhuri et al., 2018; Luarte et al., 2020). It also appears that ADEVs influence neurite outgrowth, guide axons, are involved in the potentiation, and help in the biogenesis of synapses. Furthermore, the treatment of ADEVs with interleukin-10 (IL-10) regulates the signaling of gap junction and cAMP-response element binding protein (CREB) (Datta Chaudhuri et al., 2020). Along with the different proteins, lipids, and nucleotide cargo, ADEVs also carry neurotoxic factors such as human immunodeficiency virus (HIV)-related neurotoxic proteins (Katuri et al., 2019).

Various proteins have been reported to damage the CNS. One example is negative regulatory factor (Nef) protein. Nef is a small protein expressed abundantly in astrocytes of HIV-1-infected brains and are released in ADEVs. These Nef-containing ADEVs play a significant role in the pathogenesis of HIV-associated neurological disorders (Saribas et al., 2017).

Additionally, the loss of excitatory and inhibitory synapses can be due to an uptake of ADEVs by hippocampal neurons through increased expression and the release of several miRNAs (Hu et al., 2020). A recent study also observed the modulation of neuronal uptake, differentiation, and firing by activated human ADEVs (You et al., 2019). Current literature has demonstrated the therapeutic and toxic potential of ADEVs, which suggests the need for further investigation on the impacts of ADEVs on glia-neuron communication.

Multifunctional oligodendrocytes insulate the axon by producing the myelin sheath, which depends on bidirectional glia-neuron communication (Sherman and Brophy, 2005; Nave, 2010). Other functions of oligodendrocytes include controlling the extracellular ion balance, participating in the BBB, participating in the repairing and scarring processes after CNS injuries, and providing trophic support to neurons. Oligodendrocytes release EVs and heterogeneous compositions of oligodendrocyte-derived EVs (ODEVs), which have been proven to play a crucial role in pathological functions (Falchi et al., 2013). A novel mode of bidirectional glia-neuron communication through ODEVs, particularly exosomes, has been established in a mouse model (Frühbeis et al., 2013a). ATP-triggered activation of P2 × 7 receptors and the subsequent action of acid sphingomyelinase evoke ODEV secretion, particularly in microvesicles (Bianco et al., 2009). Calcium treatment induces the release of ODEVs and is reported to carry major proteins involved in myelin, such as proteolipid protein, CNP, myelin basic protein, and myelin-oligodendrocyte glycoprotein (Krämer-Albers et al., 2007). Interestingly, the ODEVs lacking these proteins have been suggested to be impaired (Frühbeis et al., 2013a). Studies show that the promyelinating effect of the neuronal-conditioned medium is counteracted by ODEVs (Reiter and Bongarzone, 2020). The release of glutamate by electrically active axons stimulates the calcium ion entry through oligodendroglial glutamate receptors, which activates the release of ODEVs, particularly exosomes and neurons, and internalizes them by using their cargo (Frühbeis et al., 2013a). Active neurons pass demand signals to oligodendrocytes to deliver the supportive biomolecules through ODEVs, which transfer metabolites, protective proteins, glycolytic enzymes, mRNA, and miRNA to axons contributing to the maintenance of axonal integrity (Frühbeis et al., 2013a). The uptake of ODEVs by neurons results in EV-content retrieval, leading to multiple effects on neurons. Subsequently, the therapeutic effects of ODEVs on stressed neurons include restored, faster axonal transport compared to untreated neurons and neurons treated with EVs from other sources. Therefore, studies suggest that the neuroprotective effects of ODEVs maintain vital cellular functions (Frühbeis et al., 2013a; Fröhlich et al., 2014; Krämer-Albers, 2021). The promotion of fast axonal transport and its maintenance in starving neurons have also been associated with ODEVs (Frühbeis et al., 2020). Together, these studies indicate that ODEVs contribute a wide range of functions in glia-neuron communication, including long-term maintenance of neurons, axonal transport, myelin diseases, and loss of axonal integrity.

Microglia are found throughout the brain and the spinal cord and act as the first line of defense in the brain as resident macrophages (Lawson et al., 1992; Kreutzberg, 1995; Ginhoux et al., 2013; Filiano et al., 2015). Studies report that intercellular communication by microglia in both physiological and pathological conditions involves biomolecules secreted through microglial EVs (MGEVs) (Paolicelli et al., 2019). Several studies report the existence of MGEVs (Verderio et al., 2012; Garzetti et al., 2014) and their active role in glia-neuron communication in various pathological and physiological conditions, including neurodegenerative processes (Paolicelli et al., 2019). Recent studies report the detrimental and protective effects of MGEVs on myelin injuries. Enhanced excitatory transmission, neuronal production, and modulation of synaptic activity through ceramide and sphingosine synthesis induction have been associated with the interaction of MGEVs and neurons, which suggests the role of MGEVs in glia-neuron communication (Antonucci et al., 2012; Turola et al., 2012; Paolicelli et al., 2019). MGEVs, particularly exosomes, have been associated with various mental disorders, such as depression, anxiety, bipolar disorder, and schizophrenia (Saeedi et al., 2019). Recent studies suggested the neuroinflammatory role of misfolded and inflammatory proteins and the neurotoxic potential of MGEVs (Pascual et al., 2020). Additionally, the endocannabinoid N-arachidonoylethanolamine are carried by MGEVs, stimulating the cannabinoid receptor 1 of GABAergic neurons and contributing to the inhibition of presynaptic transmissions (Gabrielli et al., 2015). Proteomic analysis suggests that MGEVs carry some unique markers, such as aminopeptidase CD13 and the lactate transporter MCT-1 (Potolicchio et al., 2005). Regulation and propagation of neuroinflammatory responses in the CNS have also been associated with MGEVs through pro-inflammatory cytokines and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (Bianco et al., 2005; Takenouchi et al., 2015). Subsequently, the treatment of microglia with lipopolysaccharide has also been associated with altered production of MGEVs (Yang et al., 2018). Additionally, MGEVs with P2 × 7 receptors reduce apoptosis (Turola et al., 2012), which suggests the need to study MGEVs for potential biomarkers of various chronic neurodegenerative diseases (Panaro et al., 2020; Aires et al., 2021). In Alzheimer’s disease, MGEVs have positive and negative effects (Trotta et al., 2018). Similarly, miRNA carried by MGEVs is associated with neurodegeneration in amyotrophic lateral sclerosis (Christoforidou et al., 2020). Tumor necrosis factor production through MGEVs was also found to alter neuronal functions (Raffaele et al., 2020). Recent studies also associated the communication of neural progenitor cells (NPCs) and microglia with MGEVs and EVs released from NPCs (Cossetti et al., 2012; Pluchino and Cossetti, 2013; Cossetti et al., 2014; Matarredona et al., 2018).

The majority of proliferative cells outside neurogenic niches in the adult CNS comprise neural progenitors expressing chondroitin sulfate proteoglycan 4, which are known as NG2 glial cells (also referred to as OPCs or polydendrocytes) (Nishiyama et al., 1999; Dawson et al., 2003; Nishiyama et al., 2014; Nakano et al., 2017). NG2 glial cells have an important role in remyelination as they have the ability to proliferate and differentiate after a demyelinating insult. In CNS injuries and neurodegenerative diseases, NG2 glial cells rapidly proliferate and migrate to restore their population in focal cellular loss (McTigue et al., 2001; Nishiyama et al., 2009; Kang et al., 2010; Hughes et al., 2013). NG2-glial cells-derived EVs are reported as the important intercellular transporter of retinoic acid and enable the cross talk between NG2 glial cells and neurons to mediate remyelination and axonal/neurite outgrowth (Goncalves et al., 2019; Bahram Sangani et al., 2021). However, limited literature is available describing the role of EVs in neuron-NG2 glial cell communication.

Schwann cells support maintenance and regenerative responses of axons by diverse mechanisms of intercellular communication. A crucial role of SCs has been established in the regulation of a variety of passive axonal functions, including myelin formation with subsequent elevation in the conduction velocity, and active axonal functions, including sodium channel enrichment, internodal distance specifications, and metabolic maintenance (Court et al., 2004; Hartline and Colman, 2007; Nave and Trapp, 2008; Voas et al., 2009; Feldman et al., 2017).

Schwann cells-derived EVs (SDEVs) are also secreted from different phenotypic SCs and carry distinct protein and nucleic acid cargoes that exert either a neuroprotective or a pathological effect on the recipient cells (Wong et al., 2022). In addition to the classical mechanism of axonal communication of SCs, SDEVs mediate the lateral molecular cargo transfer from SCs to axons (Court et al., 2008; Lopez-Verrilli et al., 2013; López-Leal et al., 2020). SDEVs have also been found to be taken by peripheral axons to increase neurite sprouting of sensory neurons in vitro and to regenerate axons by 50% following neuronal injury in vivo (Lopez-Verrilli et al., 2013; López-Leal et al., 2020). SDEVs have also been found to carry and transfer p53 to axons (Lopez-Verrilli et al., 2013). The p75 neurotrophin receptor (p75^NTR) plays a key role in the SC-axon myelination during development and may arbitrate cell survival and cytoskeletal remodeling via p53 or induce cell death via c-Jun N-terminal kinase pathway activation (Cosgaya et al., 2002; Chao, 2003). SDEVs play a regulatory role in the homeostasis of different cell types of the PNS through p75^NTR and sortilin is identified by a small RNA profile (Gonçalves et al., 2020). EVs from skin precursor-derived SCs have been demonstrated to play a crucial role in axonal regrowth and regeneration of neurons (Wu et al., 2020) and repair of peripheral nerve defects by nerve grafts (Yu et al., 2021). Similarly, the transfer of RNA through EVs secreted by SC-like differentiated adipose stem cells has been shown to promote neurite outgrowth (Ching et al., 2018). The proliferation and maintenance of human dental pulp cells have also been shown to be promoted by SDEVs (Li et al., 2022).

In addition to their physiological roles, SDEVs have also been shown to exhibit pathological impact. SDEVs from high glucose-stimulated SCs have been reported to involve in mediating the development of diabetic peripheral neuropathy in a diabetic mouse model (Jia et al., 2018). SDEVs are also reported to be involved in the development of age-related schwannomatosis (a rare genetic disorder that results in tumors that grow on the peripheral nerves throughout the body) (Chignon-Sicard et al., 2019). These compelling findings elucidate the importance of SDEVs in glia-neuron cross talk both in health and in pathological conditions.

The surface of neurons cell bodies in the ganglia of the PNS is covered by SGCs that are found in sensory, sympathetic, and parasympathetic ganglia. SGCs have a variety of functions, including the regulation of the microenvironment of sympathetic ganglia (Hanani and Spray, 2020). A recent study reported that SGCs shed vesicles in the size range of exosomes and alter their protein profile under inflammatory conditions in vitro (Vinterhøj et al., 2019). However, the relevance of SGC-derived EVs in glia-neuron communication is still in its infancy and requires further studies.

Radial glial cells are progenitor cells of a bipolar shape with the specialized function of producing neurons and certain glia, including astrocytes and oligodendrocytes (Noctor et al., 2001; Rakic, 2009; Beattie and Hippenmeyer, 2017). Long radial processes of RGCs facilitate the transfer of newly produced neurons to their final destination (Rakic, 1972; Campbell and Götz, 2002). The third ventricle of the brain and the floor of the fourth ventricle possess special ependymal cells called tanycytes, which extend into the hypothalamus (Jansen et al., 1982; Wittkowski, 1998; Rodríguez-Rodríguez et al., 2019). The posterior part of the pituitary gland contains some glial cells, called pituicytes, which release and store neurohypophysial hormones (Hatton et al., 1984; Hatton, 1988).

So far, no studies have shown the role of EVs secreted from these glial cells. However, given their diverse physiological functions such as neurogenesis, neuronal migration, and maintenance of permeable neurovascular interfaces (Goodman and Hajihosseini, 2015; Anbalagan et al., 2018; Berg et al., 2018), it is imperative to explore the role of EVs secreted by these cells in future studies.