The Role of Extracellular Vesicles in the Developing Brain: Current Perspective and Promising Source of Biomarkers and Therapy for Perinatal Brain Injury

Abstract

This comprehensive review focuses on our current understanding of the proposed physiological and pathological functions of extracellular vesicles (EVs) in the developing brain. Furthermore, since EVs have attracted great interest as potential novel cell-free therapeutics, we discuss advances in the knowledge of stem cell- and astrocyte-derived EVs in relation to their potential for protection and repair following perinatal brain injury. This review identified 13 peer-reviewed studies evaluating the efficacy of EVs in animal models of perinatal brain injury; 12/13 utilized mesenchymal stem cell-derived EVs (MSC-EVs) and 1/13 utilized astrocyte-derived EVs. Animal model, method of EV isolation and size, route, timing, and dose administered varied between studies. Notwithstanding, EV treatment either improved and/or preserved perinatal brain structures both macroscopically and microscopically. Additionally, EV treatment modulated inflammatory responses and improved brain function. Collectively this suggests EVs can ameliorate, or repair damage associated with perinatal brain injury. These findings warrant further investigation to identify the optimal cell numbers, source, and dosage regimens of EVs, including long-term effects on functional outcomes.

Gut-Brain cross talk: The pathogenesis of neurodevelopmental impairment in necrotizing enterocolitis

“…Once pathogenic signals have travelled through the vagus nerve and/or inflammatory mediators have reached the CNS, the brain becomes especially susceptible to injury. This process includes activation of microglia ( via TLR4 stimulation) and subsequently astrocytes and glial cells within the brain ( 70 ). Activated microglia and astrocytes migrate to sites of injury and begin the neuroinflammatory cascade by releasing pro-inflammatory cytokines such as TNF-α, interleukin-1β (IL-1β), and interleukin-6 (IL-6) ( 70 – 73 ).…”

“…This process includes activation of microglia ( via TLR4 stimulation) and subsequently astrocytes and glial cells within the brain ( 70 ). Activated microglia and astrocytes migrate to sites of injury and begin the neuroinflammatory cascade by releasing pro-inflammatory cytokines such as TNF-α, interleukin-1β (IL-1β), and interleukin-6 (IL-6) ( 70 – 73 ). The BBB (already weakened by SCFA release) is further destabilized by the release of cytokines and the inflammatory activation of enzymes such as matrix metallopeptidases (MMPs), which allows systemic leukocytes to enter and further exacerbate injury.…”

“…The BBB (already weakened by SCFA release) is further destabilized by the release of cytokines and the inflammatory activation of enzymes such as matrix metallopeptidases (MMPs), which allows systemic leukocytes to enter and further exacerbate injury. This interplay is believed to cause abnormalities in normal myelination and white matter injury ( 70 , 73 ). At the cellular level, white matter injury is defined by alterations in the developing oligodendrocytes and specifically the pre-myelinating oligodendrocyte cell which results in hypomyelination ( 38 , 73 ).…”

Tumor-Derived Extracellular Vesicles Regulate Cancer Progression in the Tumor Microenvironment

“…EVs are closely related to the physical and pathological processes of diseases, especially cancer ( Wu et al, 2017 ; Burnouf et al, 2019 ; Gamage and Fraser, 2021 ). Tumor growth requires constant nutrients and oxygen delivered from the vascular network, as they cannot grow above 2 mm 2 with an inadequate vascular supply ( Small et al, 2014 ).…”

Extracellular Vesicles-Based Cell-Cell Communication in Melanoma: New Perspectives in Diagnostics and Therapy

“…By transferring their cargo, EVs regulate recipient cell function. They play important roles in angiogenesis [ 9 , 10 ], the regulation of metabolism [ 11 ], fertilization [ 12 ], trophoblast implantation [ 13 ], pregnancy [ 14 ], neuronal differentiation [ 15 ], regeneration, synaptic plasticity, neural trophic support, the regulation of myelination [ 16 ], dendritic spine formation, maintaining blood-brain barrier integrity [ 17 ], and immunomodulation, including the suppression of the maternal immune system by the fetus and the modulation of the infant’s immune system by maternal milk-derived exosomes [ 18 , 19 , 20 ]. The involvement of intercellular communication through exosomes in pathological processes, particularly carcinogenesis, but also neurodegeneration and inflammatory diseases, has attracted great attention of researchers.…”