The Emerging Role of Extracellular Vesicle Derived From Neurons/Neurogliocytes in Central Nervous System Diseases: Novel Insights Into Ischemic Stroke

Abstract

Neurons and neurogliocytes (oligodendrocytes, astrocytes, and microglia) are essential for maintaining homeostasis of the microenvironment in the central nervous system (CNS). These cells have been shown to support cell-cell communication via multiple mechanisms, most recently by the release of extracellular vesicles (EVs). Since EVs carry a variety of cargoes of nucleic acids, lipids, and proteins and mediate intercellular communication, they have been the hotspot of diagnosis and treatment. The mechanisms underlying CNS disorders include angiogenesis, autophagy, apoptosis, cell death, and inflammation, and cell-EVs have been revealed to be involved in these pathological processes. Ischemic stroke is one of the most common causes of death and disability worldwide. It results in serious neurological and physical dysfunction and even leads to heavy economic and social burdens. Although a large number of researchers have reported that EVs derived from these cells play a vital role in regulating multiple pathological mechanisms in ischemic stroke, the specific interactional relationships and mechanisms between specific cell-EVs and stroke treatment have not been clearly described. This review aims to summarize the therapeutic effects and mechanisms of action of specific cell-EVs on ischemia. Additionally, this study emphasizes that these EVs are involved in stroke treatment by inhibiting and activating various signaling pathways such as ncRNAs, TGF-β1, and NF-κB.

Effects of extracellular vesicles for ischemic stroke: A meta‑analysis of preclinical studies

“…To date, there are studies that suggest that miRNAs may be candidates for innovative gene therapy, playing multiple roles in promoting neurogenesis, angiogenesis and neuroplasticity. The delivery system for miRNAs has been developed to improve the biologic efficiency (39). In the studies included in the present meta-analysis, six related miRNAs were involved, namely miR-124 (25,28), miR-26a (22), miR-132 ( 27), miR-206 (32), miR-23a-3p (30), miR-135a-5p (29).…”

Microglia–neuron–vascular interactions in ischemia

“…Ischemic neuronal depolarization leads to the excessive release of excitatory neurotransmitters (mainly glutamate) causing overt Ca 2+ influx, loss of potassium, spreading depolarization, change of pH (Zöllner, 2015), release of nitric‐oxide, mitochondrial dysfunction and subsequent release of mitochondrial and inflammatory mediators (Krajewski, 1999), translocation of phosphatidylinositol (PI) to the outer leaflet of the plasma membrane, and finally disintegration of membrane‐bound compartments (Taxin, 2014, Tuo, 2022). These processes are accompanied by several subcellular changes, for instance, declustering of Kv‐channels (voltage‐dependent potassium channels) in neuronal membranes (Cserep et al, 2020), increased ROS‐production, ATP and purine nucleotides released from the neurons, changes in mitochondrion‐associated membrane contact sites, endoplasmic reticulum (ER)‐stress (Han, Jiang, et al, 2021; Han, Yuan, et al, 2021; Tajiri et al, 2004), mitochondrial fragmentation (Cserep et al, 2020; Kislin et al, 2017; Solenski, 2002), and release of extracellular vesicles (Korvenlaita, 2023; Li et al, 2022). Ischemic brain injury is complex and its mechanisms (as also outlined above and below) go well beyond the primary events of neuronal death, which may take place rapidly in the core of the lesion, or in the form of delayed neuronal death in penumbral or even remote tissues up to several days after stroke.…”

“…These processes are accompanied by several subcellular changes, for instance, declustering of Kv-channels (voltage-dependent potassium channels) in neuronal membranes (Cserep et al, 2020), increased ROS-production, ATP and purine nucleotides released from the neurons, changes in mitochondrion-associated membrane contact sites, endoplasmic reticulum (ER)-stress (Han, Jiang, et al, 2021;Han, Yuan, et al, 2021;Tajiri et al, 2004), mitochondrial fragmentation (Cserep et al, 2020;Kislin et al, 2017;Solenski, 2002), and release of extracellular vesicles (Korvenlaita, 2023;Li et al, 2022). Ischemic brain injury is complex and its mechanisms (as also outlined above and below) go well beyond the primary events of neuronal death, which may take place rapidly in the core of the lesion, or in the form of delayed neuronal death in penumbral or even remote tissues up to several days after stroke.…”

Mesenchymal stem cell therapy for ischemic stroke: Novel insight into the crosstalk with immune cells

“…EVs, the membrane-enclosed nanoscale particles secreted by all eukaryotes, always serve as a variety of molecular cargoes, such as peptides, lipids, proteins, and noncoding RNAs ( 43 , 110 ). Based on the size of EVs, they can be divided into three subtypes: exosomes, microvesicles, and apoptotic bodies ( 111 ). Exosomes with a diameter of 30–150 nm form via the fusion of multivesicular bodies with membrane and are further released into the extracellular matrix ( 112 , 113 ).…”

“…Microvesicles with a diameter of 200–1,000 nm are produced owing to the outward budding of the plasma membrane ( 112 , 113 ). Conversely, apoptotic bodies with a diameter of 1,000–5,000 nm are produced by dying cells and are even more abundant than the two other particles ( 111 ). Only exosomes and microvesicles are relevant to the therapeutic effects imparted by MSC-EVs.…”