Although stem cell-based therapy has demonstrated considerable potential to manage certain diseases more successfully than conventional surgery, it nevertheless comes with inescapable drawbacks that might limit its clinical translation. Compared to stem cells, stem cell-derived exosomes possess numerous advantages, such as non-immunogenicity, non-infusion toxicity, easy access, effortless preservation, and freedom from tumorigenic potential and ethical issues. Exosomes can inherit similar therapeutic effects from their parental cells such as embryonic stem cells and adult stem cells through vertical delivery of their pluripotency or multipotency. After a thorough search and meticulous dissection of relevant literature from the last five years, we present this comprehensive, up-to-date, specialty-specific and disease-oriented review to highlight the surgical application and potential of stem cell-derived exosomes. Exosomes derived from stem cells (e.g., embryonic, induced pluripotent, hematopoietic, mesenchymal, neural, and endothelial stem cells) are capable of treating numerous diseases encountered in orthopedic surgery, neurosurgery, plastic surgery, general surgery, cardiothoracic surgery, urology, head and neck surgery, ophthalmology, and obstetrics and gynecology. The diverse therapeutic effects of stem cells-derived exosomes are a hierarchical translation through tissue-specific responses, and cell-specific molecular signaling pathways. In this review, we highlight stem cell-derived exosomes as a viable and potent alternative to stem cell-based therapy in managing various surgical conditions. We recommend that future research combines wisdoms from surgeons, nanomedicine practitioners, and stem cell researchers in this relevant and intriguing research area.

Glutaminase 1 is the main enzyme responsible for glutamate production in mammalian cells. The roles of macrophage and microglia glutaminases in brain injury, infection, and inflammation are well documented. However, little is known about the regulation of neuronal glutaminase, despite neurons being a predominant cell type of glutaminase expression. Using primary rat and human neuronal cultures, we confirmed that interleukin‐1β (IL‐1β) and tumor necrosis factor‐α (TNF‐α), two pro‐inflammatory cytokines that are typically elevated in neurodegenerative disease states, induced neuronal death and apoptosis in vitro. Furthermore, both intracellular and extracellular glutamate levels were significantly elevated following IL‐1β and/or TNF‐α treatment. Pre‐treatment with N‐Methyl‐d‐aspartate (NMDA) receptor antagonist MK‐801 blocked cytokine‐induced glutamate production and alleviated the neurotoxicity, indicating that IL‐1β and/or TNF‐α induce neurotoxicity through glutamate. To determine the potential source of excess glutamate production in the culture during inflammation, we investigated the neuronal glutaminase and found that treatment with IL‐1β or TNF‐α significantly upregulated the kidney‐type glutaminase (KGA), a glutaminase 1 isoform, in primary human neurons. The up‐regulation of neuronal glutaminase was also demonstrated in situ in a murine model of HIV‐1 encephalitis. In addition, IL‐1β or TNF‐α treatment increased the levels of KGA in cytosol and TNF‐α specifically increased KGA levels in the extracellular fluid, away from its main residence in mitochondria. Together, these findings support neuronal glutaminase as a potential component of neurotoxicity during inflammation and that modulation of glutaminase may provide therapeutic avenues for neurodegenerative diseases.

Brain inflammation is a complex cellular and molecular response to stress, injury or infection of the CNS in attempt to defend against insults, clear dead and damaged neurons and return the CNS to a normal state. Inflammation in the CNS is driven by the activation of resident microglia, astrocytes and infiltrating peripheral macrophages, which release a plethora of anti‐ and pro‐inflammatory cytokines, chemokines, neurotransmitters and reactive oxygen species. This inflammatory state inadvertently causes further bystander damage to neurons and produces both detrimental and favorable conditions for neurogenesis. Inflammatory factors have varying effects on neural progenitor cell proliferation, migration, differentiation, survival and incorporation of newly born neurons into the CNS circuitry. The unique profile of inflammatory factors, which depends on the severity of inflammation, can have varying consequences on neurogenesis. Inflammatory factors released during mild acute inflammation usually stimulate neurogenesis; where as the factors released by uncontrolled inflammation create an environment that is detrimental to neurogenesis. This review will provide a summary of current progress in this emerging field and examine the potential mechanisms through which inflammation affects neurogenesis during neurological complications.

Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly globally. Emerging evidence has demonstrated microglia-driven neuroinflammation as a key contributor to the onset and progression of AD, however, the mechanisms that mediate neuroinflammation remain largely unknown. Recent studies have suggested mitochondrial dysfunction including mitochondrial DNA (mtDNA) damage, metabolic defects, and quality control (QC) disorders precedes microglial activation and subsequent neuroinflammation. Therefore, an in-depth understanding of the relationship between mitochondrial dysfunction and microglial activation in AD is important to unveil the pathogenesis of AD and develop effective approaches for early AD diagnosis and treatment. In this review, we summarized current progress in the roles of mtDNA, mitochondrial metabolism, mitochondrial QC changes in microglial activation in AD, and provide comprehensive thoughts for targeting microglial mitochondria as potential therapeutic strategies of AD.

Exosomes are small bilipid layer-enclosed extracellular vesicles that can be found in tissues and biological fluids. As a key cell-to-cell and distant communication mediator, exosomes are involved in various central nervous system (CNS) diseases, potentially through transferring their contents such as proteins, lipids and nucleic acids to the target cells. Exosomal miRNAs, which are small non-coding RNAs in the exosomes, are known to be more stable than free miRNAs and therefore have lasting effects on disease-related gene expressions. There are distinct profiles of exosomal miRNAs in different types of CNS diseases even before the onset of irreversible neurological damages, indicating that exosomal miRNAs within tissues and biological fluids could serve as promising biomarkers. Emerging evidence has also demonstrated the pathological effects of several exosomal miRNAs in CNS diseases via specific modulation of disease-related factors. Moreover, exosomes carry therapeutically beneficial miRNAs across the blood-brain-barrier, which can be exploited as a powerful drug delivery tool to help alleviating multiple CNS diseases. In this review, we summarize the recent progress made in understanding the biological roles of exosomal miRNAs as potential diagnostic biomarkers, pathological regulators, and therapeutic targets/drugs for CNS diseases. A comprehensive discussion of the main concerns and challenges for the applications of exosomal miRNAs in the clinical setting is also provided.

Exposure to atmospheric particulate matter PM_2.5 (aerodynamic diameter ≤ 2.5 μm) has been epidemiologically associated with respiratory illnesses. However, recent data have suggested that PM_2.5 is able to infiltrate into circulation and elicit a systemic inflammatory response. Potential adverse effects of air pollutants to the central nervous system (CNS) have raised concerns, but whether PM_2.5 causes neurotoxicity remains unclear. In this study, we have demonstrated that PM_2.5 impairs the tight junction of endothelial cells and increases permeability and monocyte transmigration across endothelial monolayer in vitro, indicating that PM_2.5 is able to disrupt blood–brain barrier integrity and gain access to the CNS. Exposure of primary neuronal cultures to PM_2.5 resulted in decrease in cell viability and loss of neuronal antigens. Furthermore, supernatants collected from PM_2.5‐treated macrophages and microglia were also neurotoxic. These macrophages and microglia significantly increased extracellular levels of glutamate following PM_2.5 exposure, which were negatively correlated with neuronal viability. Pre‐treatment with NMDA receptor antagonist MK801 alleviated neuron loss, suggesting that PM_2.5 neurotoxicity is mediated by glutamate. To determine the potential source of excess glutamate production, we investigated glutaminase, the main enzyme for glutamate generation. Glutaminase was reduced in PM_2.5‐treated macrophages and increased in extracellular vesicles, suggesting that PM_2.5 induces glutaminase release through extracellular vesicles. In conclusion, these findings indicate PM_2.5 as a potential neurotoxic factor, crucial to understanding the effects of air pollution on the CNS. image We propose the following cascade of events for PM_2.5‐induced neurotoxicity: PM_2.5 is inhalable and able to infiltrate into circulation. Circulating PM_2.5 impairs tight junction of endothelial cells, disrupts blood–brain barrier integrity, and gains access to the central nervous system. PM_2.5 induces neuronal injury directly or through macrophages and microglia by the elevated production of glutamate. The discovery of this cascade of events supports an adverse effect of air pollution on the central nervous system.