Dopaminergic neuron loss caused by microglia activation is an important pathological factor of Parkinson's disease (PD). Previously, we reported that small extracellular vesicle from adipose derived stem cells (ADSC-sEVs) could inhibit the activation of microglia and protect neuron apoptosis from microglia activation. However, whether ADSC-sEVs have protective effect on the motor deficit of PD mouse and the exact mechanism remains unknown. In this study, ADSC-sEVs were delivered to experimental model of Parkinson's disease by tail vein injection to explore the in vivo effect of ADSC-sEVs on PD. Next, the potential key microRNA in ADSC-sEVs was screened by RNA sequencing (RNA-seq), and the exact mechanism was further explored. We found that ADSC-sEVs greatly alleviated the activation of microglia and reduced the loss of dopaminergic neurons in the substantia nigra of PD mice, the motor deficit was also significantly improved. By RNA-seq analysis, miR-100-5p was verified as a potential microRNA in this process, because knockdown of miR-100-5p in ADSC-sEVs weakened the protective effect of ADSC-sEVs on PD mouse as well as the anti-inflammatory effect on microglia activation. Finally, we found that miR-100-5p could target Deltex E3 ubiquitin ligase 3 L (DTX3L) and suppress its expression, which then decreased the expression and phosphorylation of Signal Transducers and Activators of Transcription 1 (STAT1), as well as alleviating the activation of microglia. Our findings illustrate that ADSC-sEVs are an effective therapy for PD, and it could be a promising therapy for the treatment of PD.

Subarachnoid hemorrhage leads to a series of pathological changes, including vascular spasm, cellular apoptosis, blood-brain barrier damage, cerebral edema, and white matter injury. Microglia, which are the key immune cells in the central nervous system, maintain homeostasis in the neural environment, support neurons, mediate apoptosis, participate in immune regulation, and have neuroprotective effects. Increasing evidence has shown that microglia play a pivotal role in the pathogenesis of subarachnoid hemorrhage and affect the process of injury and the prognosis of subarachnoid hemorrhage. Moreover, microglia play certain neuroprotective roles in the recovery phase of subarachnoid hemorrhage. Several approaches aimed at modulating microglia function are believed to attenuate subarachnoid hemorrhage injury. This provides new targets and ideas for the treatment of subarachnoid hemorrhage. However, an in-depth and comprehensive summary of the role of microglia after subarachnoid hemorrhage is still lacking. This review describes the activation of microglia after subarachnoid hemorrhage and their roles in the pathological processes of vasospasm, neuroinflammation, neuronal apoptosis, blood-brain barrier disruption, cerebral edema, and cerebral white matter lesions. It also discusses the neuroprotective roles of microglia during recovery from subarachnoid hemorrhage and therapeutic advances aimed at modulating microglial function after subarachnoid hemorrhage. Currently, microglia in subarachnoid hemorrhage are targeted with TLR inhibitors, nuclear factor-κB and STAT3 pathway inhibitors, glycine/tyrosine kinases, NLRP3 signaling pathway inhibitors, Gasdermin D inhibitors, vincristine receptor α receptor agonists, ferroptosis inhibitors, genetic modification techniques, stem cell therapies, and traditional Chinese medicine. However, most of these are still being evaluated at the laboratory stage. More clinical studies and data on subarachnoid hemorrhage are required to improve the treatment of subarachnoid hemorrhage.

Motor function recovery after complete spinal cord injury remained as a challenge in medical field, while one of the key approaches is promoting the local microenvironments. In this research, we performed a conjugated therapy by transplantation of neural stem cell (NSC) scaffolds and umbilical cord mesenchymal stem cell derived exosomes (ucMSC-exos) for the treatment of complete transactional spinal cord injury (SCI). We first demonstrated the anti-inflammatory effects of ucMSC-exos in vitro and found that ucMSC-exos could regulate microglia polarization from M1 to M2, an anti-inflammatory phenotype. Besides, ucMSC-exos also promoted NSC proliferation and neural differentiation during in vitro culturing. On the other hand, core-shell hydrogel microfibers were used as transplantation scaffolds for both small and large SCI defects. The core-shell microfibers could carry large amounts of NSCs in the core portion and the shell portion is highly permeable for nutrient and metabolite transportation. In in vivo experiments, we found that conjugated transplantation of ucMSC-exos and NSC microfibers could decreased inflammatory cytokines at lesion sites, gave rise to more neurons and promoted angiogenesis, thus comprehensively improved the local microenvironment while compared with transplantation of NSC scaffolds only. These beneficial results were in accordance with those in vitro experiments and further led to better locomotor function recovery. In summary, this research has demonstrated that that conjugated transplantation of ucMSC-exos and NSC microfibers could make a potential tool for complete SCI repair.

Age-related macular degeneration (AMD) is a debilitating retinal disorder that may lead to progressive vision loss. One contributing factor to AMD pathogenesis is excessive blue light (BL) exposure. In this study, we investigated the therapeutic potential of exosomes derived from human umbilical cord blood mesenchymal stem cells (hUCMSC-EXs) in addressing BL-induced damage to ARPE-19 human retinal pigment epithelial (RPE) cells and explored the underlying mechanisms. Our findings revealed that BL exposure induced morphological alterations in ARPE-19 cells, accompanied by a time-dependent decline in cell viability, increased apoptosis, heightened oxidative stress, and inflammatory responses; however, hUCMSC-EXs dose-dependently mitigated BL-induced ARPE-19 cell damage. Interestingly, hUCMSC-EXs were found to suppress the upregulation of fibroblast growth factor 2 (FGF2) in BL-exposed ARPE-19 cells. Furthermore, FGF2 overexpression partially counteracted the inhibitory effects of hUCMSC-EXs on FGF2 expression and compromised the protective benefits of hUCMSC-EXs against BL-induced ARPE-19 cell damage. In conclusion, our results suggest that hUCMSC-EXs shield ARPE-19 cells from BL-induced harm by inhibiting FGF2 expression.

Extracellular vesicles released from mesenchymal stem cells (MSCs-EV) have shown anti-inflammatory effects in Parkinson's disease (PD). This study was designed to assess the neuroprotective effects of human umbilical cord MSCs (hucMSCs) and the possible mechanisms involved. SH-SY5Y cells were induced with MPP+, and the impact of hucMSCs-EV on the damage to SH-SY5Y cells was examined. Mice were induced with PD-like symptoms by MPTP and the effects of hucMSCs-EV on neurological damage in mouse brain tissue were detected as well. HucMSCs-EV inhibited apoptosis and oxidative stress in MPP+-induced SH-SY5Y cells. HucMSCs-EV suppressed behavioral deficits and neuronal apoptosis in MPTP-induced mice, with an increased number of dopamine neurons in brain tissues and decreased p-alpha-syn expression in dopamine neurons. The expression of ribosomal protein S27A (RPS27A) in SH-SY5Y cells was elevated after co-culture of neurons and hucMSCs-EV, and RPS27A silencing abated the effect of hucMSCs-EV in vivo and in vitro. RPS27A bound to the MDM2 promoter, thus promoting P53 ubiquitination and degradation. MDM2 overexpression strengthened the therapeutic effect of hucMSCs-EV. We conclude that hucMSCs-EV promote the interaction between RPS27A and MDM2 by delivering RPS27A, which regulates the MDM2-P53 axis to promote degradation of P53 to ameliorate neurological damage in PD.

This review deals with the application of extracellular vesicles (EVs) in the treatment of various neuropsychiatric disorders, including mood disorders, neurodegeneration, psychosis, neurological insults and injuries, epilepsy and substance use disorders. The main challenges of most neuropsychiatric pharmaceuticals nowadays are how to reach the central nervous system at therapeutic concentration and maintain it long enough and how to avoid undesirable side effects caused by unsatisfying toxicity. Extracellular vesicles, as very important mediators of intercellular communication, can have a variety of therapeutic qualities. They can act neuroprotective, regenerative and anti-inflammatory, but they also have characteristics of a good drug delivery system, including their nano- scale size, biological safety and abilities to cross BBB, to pack drugs within the lipid bilayer, and not to trigger an immunological response. Besides, due to their presence in readily accessible biofluids, they are good candidates for biomarkers of the disease, its progression and therapy response monitoring. Alternations in EVs' cargo profiles can reflect the pathogenesis of neuropsychiatric disorders, but they could also affect the disease outcomes. In the future, EVs could help physicians to tailor treatment strategies for individual patients, however, more extensive studies are needed to standardize isolation, purification and production procedures, increase efficacy of drug loading and limit unwanted effects of innate EVs' content.

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) can traverse the blood-brain barrier due to their small size. This characteristic makes them a research hotspot for the treatment of Parkinson's disease (PD) and is expected to be a potentially revolutionary strategy for treating PD. Despite this, no summary of clinical trial results has been reported.

To assess the efficacy and durability of MSC-EVs in treating PD.

Systematic searches were conducted in four electronic databases until June 2024 to collect studies on the use of MSC-EVs for this purpose. Thirteen relevant randomized controlled trials, encompassing 16 experiments, were selected for inclusion.

Behavioral assessments, including the rotarod and apomorphine turning behavior tests, indicated improvements in motor coordination (P < 0.00001); the Pole test and the Wire-hang test showed enhanced limb motor agility and synchronization (P = 0.003 and P < 0.00001, respectively). Histopathologically, there was a reduction in inflammatory markers such as tumor necrosis factor-α and interleukin-6 (P = 0.03 and P = 0.01, respectively) and an increase in tyrosine hydroxylase-positive cells in the lesion areas (P < 0.00001).

MSC-EV therapy for PD is a gradual process, with significant improvements observable more than 2 weeks after administration and lasting at least 8 weeks. This study is the first to demonstrate the efficacy and durability of MSC-EV treatment in PD.

Small extracellular vesicles (sEVs) are membrane-bound vesicles with a size of less than 200 nm, released by cells. Due to their relatively small molecular weight and ability to participate in intercellular communication, sEVs can serve not only as carriers of biomarkers for disease diagnosis but also as effective drug delivery agents. Furthermore, these vesicles are involved in regulating the onset and progression of various diseases, reflecting the physiological and functional states of cells. This paper introduces the classification of extracellular vesicles, with a focus on the extraction and identification of sEVs and their significant role in repair, diagnosis, and intercellular communication. Additionally, the paper addresses the engineering modification of sEVs to provide a reference for enhanced understanding and application.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the gradual loss of dopamine-producing neurons. Oxidative stress, mitochondrial dysfunction, detrimental immune response, and neuroinflammation are mainly responsible for the injury and degeneration of dopaminergic neurons in the brains of patients suffering from PD. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as a promising therapeutic approach for treating PD due to their ability to suppress the activation of inflammatory immune cells and enhance the viability and function of dopamine-producing neurons. MSC-EVs can easily bypass the blood-brain barrier and deliver their cargo (neuroprotective factors, immunosuppressive proteins, and microRNAs) to injured dopamine-producing neurons and brain-infiltrated inflammatory immune cells. A large number of recently published experimental studies demonstrated that MSC-EVs efficiently alleviated PD-related motor and behavioral deficits in animal models, indicating that MSC-EVs should be considered as potentially new therapeutic agents for the treatment of PD. Accordingly, in this review article, we summarized current knowledge about the therapeutic potential of MSCs-EVs in the treatment of PD, paving the way for their future clinical use in the treatment of neurodegenerative and neuroinflammatory disorders.

The critical role of the immune system in brain function and dysfunction is well recognized, yet development of immune therapies for psychiatric diseases has been slow due to concerns about iatrogenic immune deficiencies. These concerns are emphasized by the lack of objective diagnostic tools in psychiatry. A promise to resolve this conundrum lies in the exploitation of extracellular vesicles (EVs) that are physiologically produced or can be synthetized. EVs regulate recipient cell functions and offer potential for EVs-based therapies. Intranasal EVs administration enables the targeting of specific brain regions and functions, thereby facilitating the design of precise treatments for psychiatric diseases. The development of such therapies requires navigating four dynamically interacting networks: neuronal, glial, immune, and EVs. These networks are profoundly influenced by brain fluid distribution. They are crucial for homeostasis, cellular functions, and intercellular communication. Fluid abnormalities, like edema or altered cerebrospinal fluid (CSF) dynamics, disrupt these networks, thereby negatively impacting brain health. A deeper understanding of the above-mentioned four dynamically interacting networks is vital for creating diagnostic biomarker panels to identify distinct patient subsets with similar neuro-behavioral symptoms. Testing the functional pathways of these biomarkers could lead to new therapeutic tools. Regulatory approval will depend on robust preclinical data reflecting progress in these interdisciplinary areas, which could pave the way for the design of innovative and precise treatments. Highly collaborative interdisciplinary teams will be needed to achieve these ambitious goals.

JOURNAL/nrgr/04.03/01300535-202504000-00027/figure1/v/2024-07-06T104127Z/r/image-tiff Cardiac arrest can lead to severe neurological impairment as a result of inflammation, mitochondrial dysfunction, and post-cardiopulmonary resuscitation neurological damage. Hypoxic preconditioning has been shown to improve migration and survival of bone marrow-derived mesenchymal stem cells and reduce pyroptosis after cardiac arrest, but the specific mechanisms by which hypoxia-preconditioned bone marrow-derived mesenchymal stem cells protect against brain injury after cardiac arrest are unknown. To this end, we established an in vitro co-culture model of bone marrow-derived mesenchymal stem cells and oxygen-glucose deprived primary neurons and found that hypoxic preconditioning enhanced the protective effect of bone marrow stromal stem cells against neuronal pyroptosis, possibly through inhibition of the MAPK and nuclear factor κB pathways. Subsequently, we transplanted hypoxia-preconditioned bone marrow-derived mesenchymal stem cells into the lateral ventricle after the return of spontaneous circulation in an 8-minute cardiac arrest rat model induced by asphyxia. The results showed that hypoxia-preconditioned bone marrow-derived mesenchymal stem cells significantly reduced cardiac arrest-induced neuronal pyroptosis, oxidative stress, and mitochondrial damage, whereas knockdown of the liver isoform of phosphofructokinase in bone marrow-derived mesenchymal stem cells inhibited these effects. To conclude, hypoxia-preconditioned bone marrow-derived mesenchymal stem cells offer a promising therapeutic approach for neuronal injury following cardiac arrest, and their beneficial effects are potentially associated with increased expression of the liver isoform of phosphofructokinase following hypoxic preconditioning.

Small extracellular vesicles (sEVs), including exosomes as a subtype, with a diameter typically less than 200 nm and originating from the endosomal system, are capable of transporting a diverse array of bioactive molecules, including proteins, nucleic acids, and lipids, thereby facilitating intercellular communication and modulating cellular functions. Vascular dementia (VaD) represents a form of cognitive impairment attributed to cerebrovascular disease, characterized by a complex and multifaceted pathophysiological mechanism. Currently, the therapeutic approach to VaD predominantly emphasizes symptom management, as no specific pharmacological treatment exists to cure the condition. Recent investigations have illuminated the significant role of sEVs in the pathogenesis of vascular dementia. This review seeks to provide a comprehensive analysis of the characteristics and functions of sEVs, with a particular focus on their involvement in vascular dementia and its underlying mechanisms. The objective is to advance the understanding of the interplays between sEVs and vascular dementia, thereby offering novel insights for future research and therapeutic strategies.

Parkinson's disease (PD) is a neurodegenerative disorder that gets exacerbated by vascular injury. Neural stem cell-derived exosomes (NSC-Exos) display effective neuroprotective properties in PD models. Cell division control protein 42 (CDC42) is connected to angiogenesis, but its effects in PD remain undefined. This research aims to reveal the role of CDC42 in PD. First, we applied 1-methyl-4-phenylpyridinium (MPP+) to induce the human cerebral microvascular endothelial cells (HCMECs) model and evaluated cell viability and ferroptosis. Then, we characterized NSC-Exos. Next, to appraise the effect of hypoxia-pretreated NSC-Exos (H-NSC-Exos) on the MPP+-induced cells model, we examined angiogenesis and ferroptosis in HCMECs. Moreover, we constructed the PD mice model using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and tested the behavioral experiments and vascular injury of mice. Furthermore, we examined cellular ferroptosis and angiogenesis after knockdown of CDC42. Additionally, we investigated the interaction of CDC42 with Acyl-CoA synthetase long-chain family member 4 (ACSL4) and detected cellular ferroptosis and angiogenesis after overexpression of ACSL4. We found that H-NSC-Exos reversed the MPP+-induced decrease in HCMECs viability and migration, lowered lipid-reactive oxygen species (lipid-ROS) levels, suppressed ferroptosis, and facilitated angiogenesis. Moreover, H-NSC-Exos attenuated MPTP-induced PD development, vascular injury, and ferroptosis in mice. H-NSC-Exos with the knockdown of CDC42 reduced cell viability and angiogenesis and raised ferroptosis and lipid-ROS levels, which were reversed by ferrostatin-1 and liproxstatin-1. CDC42 interacted with ACSL4. Furthermore, overexpression of ACSL4 aggravated the above effects of H-NSC-Exos in which CDC42 was knocked down. Our study reveals that H-NSC-Exos-derived CDC42 inhibited ACSL4-related ferroptosis to alleviate vascular injury in PD mice models. CDC42 may serve as a potent therapeutic target for PD treatment.

Parkinson's disease (PD) is a progressive neurodegenerative disorder with symptoms including tremor and bradykinesia, while traditional dopamine replacement therapy and hypothalamic deep brain stimulation can temporarily relieve patients' symptoms, they cannot cure the disease. Hence, discovering new methods is crucial to designing more effective therapeutic approaches to address the condition. In our previous study, we found that exosomes (Exos) derived from human umbilical cord mesenchymal stem cells (hucMSCs) repaired a PD model by inducing dopaminergic neuron autophagy and inhibiting microglia. However, it is not clear whether its therapeutic effect is related to inhibiting apoptosis by inhibiting caspase-3 expression.

Three intervention schemes were used concerning previous literature, and the dosage of each scheme is the same, with different dosing intervals and treatment courses and to compare the aspects of behavior, histomorphology, and biochemical indexes. To predict and determine target gene enrichment, high-throughput sequencing and miRNA expression profiling of exosomes, GO and KEGG analysis, and Western blot were used.

Exos labeled with PKH67 were found to reach the substantia nigra through the bloodbrain barrier and existed in the liver and spleen. 6-hydroxydopamine (6-OHDA) induced PD rats were treated with Exos every two days for one month, which alleviated the asymmetric rotation induced by morphine, reduced the loss of dopaminergic neurons in the substantia nigra, and increased dopamine levels in the striatum. The effect became more significant as the treatment time was extended to two months. These results suggest that hucMSCs-Exos can inhibit the 6-OHDA- induced neuron damage in PD rats, and its neuroprotective effects may be mediated by inhibiting cell apoptosis. Through high-throughput sequencing of miRNA, potential targets for Exos to inhibit apoptosis may be BAD, IKBKB, TRAF2, BCL2, and CYCS.

The above results indicate that hucMSCs-Exos can inhibit 6-OHDA-induced damage in PD rats, and its neuroprotective effect may be mediated by inhibiting cell apoptosis.

The global issue of aging populations has become increasingly prominent, thus the research and development for anti-aging therapies to assure longevity as well as to ameliorate age-related complications is put high on the agenda. The young humoral milieu has been substantiated to impart youthful characteristics to aged cells or organs. Extracellular vesicles (EVs) are a heterogeneous group of cell-derived membrane-limited structures that serve as couriers of proteins and genetic material to regulate intercellular communication. Of note, EVs appeared to be an indispensable component of young blood in prolonging lifespans, and circulating EVs have been indicated to mediate the beneficial effect of a young milieu on aging. Human umbilical cord mesenchymal stem cell-derived EVs (HUCMSC-EVs), isolated from the youngest adult stem cell source, are speculated to reproduce the function of circulating EVs in young blood and partially revitalize numerous organs in old animals. Robust evidence has suggested HUCMSC-EVs as muti-target therapeutic agents in combating aging and alleviating age-related degenerative disorders. Here, we provide a comprehensive overview of the anti-aging effects of HUCMSC-EVs in brain, heart, vasculature, kidney, muscle, bone, and other organs. Furthermore, we critically discuss the current investigation on engineering strategies of HUCMSC-EVs, intending to unveil their full potential in the field of anti-aging research.

Recent years, exosomes have been increasing used to treat diseases, but there is little research on how exosomes affect the metabolism of the body after entering. Therefore, in this study, we discussed the changes of metabolic spectrum and determined the differentially expressed metabolites in the serum of cynomolgus monkeys after injecting exosomes. Six cynomolgus monkeys were divided into control group and exosomes group. After intravenous injection of exosomes, the peripheral blood serum of cynomolgus monkeys was collected at baseline, day 1, day 7 and day 14 respectively. An ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry-based non-targeted metabolomics platform was used to detect the metabolites. The metabolic spectra of two groups of cynomolgus monkeys were identified and compared, and the time series changes of metabolites in exosomes were described.

The results showed that there was significant difference in metabolic spectrum between the two groups. 45, 114, 49, 39 differentially expressed metabolites were identified in baseline, day 1, day 7, and day 14, respectively. 6-hydroxydopamine, a metabolite related to the regulation of nerve function, was also found. Tryptophan metabolism, choline metabolism in cancer, porphyrin and chlorophyll metabolism were involved in day 1. Sphingolipid metabolism and histidine metabolism were involved in day 7. Three pathways, including choline metabolism, sphingolipid metabolism and biotin metabolism in cancer were involved in day 14. Through time series analysis, it was found that the level of propionylcarnitine and biliverdin increased on day 1 after inoculation with exosomes, while the level of hippuric acid decreased. These changes of immune-related metabolites suggested that exosomes might participate in the immunoregulation reaction after entering the body of cynomolgus monkeys.

In our current study, we found that exosomes injected intravenously affect the changes of metabolites and metabolic pathways in cynomolgus monkeys. Intravenous injection of exosomes may affect the metabolite 6-hydroxydopamine, sphingolipid metabolic pathway, and choline metabolic in cancer pathway, which is of some significance for the treatment of Parkinson's disease. In addition, exosomes may also affect the immune-related metabolites in vivo, such as propionylcarnitine, biliverdin, hippuric acid metabolites, as well as tryptophan metabolism pathway, sphingolipid metabolism pathway involved in immune regulation, which is of great significance for the future study of immune-regulatory mechanisms of exosomes.

Cell-secreted nanovesicles of endosomal origin, called exosomes, are vital for mediating intracellular communication. As local or distal transporters of intracellular cargo, they reflect the unique characteristics of secretory cells and establish cell-specific interactions via characteristic surface proteins and receptors. With the advent of rapid isolation, purification, and identification techniques, exosomes have become an attractive choice for disease diagnosis (exosomal content as biomarkers), cell-free therapy, and tissue regeneration. Mesenchymal stem cell (MSC)-derived exosomes (MSC-exosomes) display angiogenic, immune-modulatory, and other therapeutic effects crucial for cytoprotection, ischemic wound repair, myocardial regeneration, etc. The primary focus of this review is to highlight the widespread application of MSC-exosomes in therapeutics, theranostics, and tissue regeneration. After a brief introduction of exosome properties, biogenesis, isolation, and functions, recent studies on therapeutic and regenerative applications of MSC-exosomes are described, focusing on bone, cartilage, periodontal, cardiovascular, skin, and nerve regeneration. Finally, the review highlights the theranostic potential of exosomes followed by challenges, summary, and outlook.

Parkinson's disease (PD) is a stressful neurodegenerative disorder affecting millions worldwide. PD leads to debilitating motor and cognitive symptoms such as tremors, rigidity, and difficulty walking. Current therapies for PD are symptomatic and don't address the root cause. Therefore, there is an urgent need for better management and intensive research into alternative therapies. Mesenchymal stem cell (MSC) therapy is among the leading contenders among these promising avenues. We examined preclinical and clinical evidence demonstrating the neuroprotective, anti-inflammatory, and regenerative properties of the MSCs. This review focuses on the complex pathophysiological mechanisms of PD, as well as the perspectives of MSCs and their derivatives, such as secretomes and exosomes, in the clinical management of PD. We also analyzed the challenges and limitations of each approach, including delivery methods, timing of administration, and long-term safety considerations.

Exosomes, as membranous vesicles generated by multiple cell types and secreted to extracellular space, play a crucial role in a range of brain injury-related brain disorders by transporting diverse proteins, RNA, DNA fragments, and other functional substances. The nervous system's pathogenic mechanisms are complicated, involving pathological processes like as inflammation, apoptosis, oxidative stress, and autophagy, all of which result in blood-brain barrier damage, cognitive impairment, and even loss of normal motor function. Exosomes have been linked to the incidence and progression of brain disorders in recent research. As a result, a thorough knowledge of the interaction between exosomes and brain diseases may lead to the development of more effective therapeutic techniques that may be implemented in the clinic. The potential role of exosomes in brain diseases and the crosstalk between exosomes and other pathogenic processes were discussed in this paper. Simultaneously, we noted the delicate events in which exosomes as a media allow the brain to communicate with other tissues and organs in physiology and disease, and compiled a list of natural compounds that modulate exosomes, in order to further improve our understanding of exosomes and propose new ideas for treating brain disorders.

JOURNAL/nrgr/04.03/01300535-202409000-00042/figure1/v/2024-01-16T170235Z/r/image-tiff Parkinson's disease is a neurodegenerative disease characterized by motor and gastrointestinal dysfunction. Gastrointestinal dysfunction can precede the onset of motor symptoms by several years. Gut microbiota dysbiosis is involved in the pathogenesis of Parkinson's disease, whether it plays a causal role in motor dysfunction, and the mechanism underlying this potential effect, remain unknown. CCAAT/enhancer binding protein β/asparagine endopeptidase (C/EBPβ/AEP) signaling, activated by bacterial endotoxin, can promote α-synuclein transcription, thereby contributing to Parkinson's disease pathology. In this study, we aimed to investigate the role of the gut microbiota in C/EBPβ/AEP signaling, α-synuclein-related pathology, and motor symptoms using a rotenone-induced mouse model of Parkinson's disease combined with antibiotic-induced microbiome depletion and fecal microbiota transplantation. We found that rotenone administration resulted in gut microbiota dysbiosis and perturbation of the intestinal barrier, as well as activation of the C/EBP/AEP pathway, α-synuclein aggregation, and tyrosine hydroxylase-positive neuron loss in the substantia nigra in mice with motor deficits. However, treatment with rotenone did not have any of these adverse effects in mice whose gut microbiota was depleted by pretreatment with antibiotics. Importantly, we found that transplanting gut microbiota derived from mice treated with rotenone induced motor deficits, intestinal inflammation, and endotoxemia. Transplantation of fecal microbiota from healthy control mice alleviated rotenone-induced motor deficits, intestinal inflammation, endotoxemia, and intestinal barrier impairment. These results highlight the vital role that gut microbiota dysbiosis plays in inducing motor deficits, C/EBPβ/AEP signaling activation, and α-synuclein-related pathology in a rotenone-induced mouse model of Parkinson's disease. Additionally, our findings suggest that supplementing with healthy microbiota may be a safe and effective treatment that could help ameliorate the progression of motor deficits in patients with Parkinson's disease.

JOURNAL/nrgr/04.03/01300535-202409000-00033/figure1/v/2024-01-16T170235Z/r/image-tiff We previously reported that miR-124-3p is markedly upregulated in microglia-derived exosomes following repetitive mild traumatic brain injury. However, its impact on neuronal endoplasmic reticulum stress following repetitive mild traumatic brain injury remains unclear. In this study, we first used an HT22 scratch injury model to mimic traumatic brain injury, then co-cultured the HT22 cells with BV2 microglia expressing high levels of miR-124-3p. We found that exosomes containing high levels of miR-124-3p attenuated apoptosis and endoplasmic reticulum stress. Furthermore, luciferase reporter assay analysis confirmed that miR-124-3p bound specifically to the endoplasmic reticulum stress-related protein IRE1α, while an IRE1α functional salvage experiment confirmed that miR-124-3p targeted IRE1α and reduced its expression, thereby inhibiting endoplasmic reticulum stress in injured neurons. Finally, we delivered microglia-derived exosomes containing miR-124-3p intranasally to a mouse model of repetitive mild traumatic brain injury and found that endoplasmic reticulum stress and apoptosis levels in hippocampal neurons were significantly reduced. These findings suggest that, after repetitive mild traumatic brain injury, miR-124-3 can be transferred from microglia-derived exosomes to injured neurons, where it exerts a neuroprotective effect by inhibiting endoplasmic reticulum stress. Therefore, microglia-derived exosomes containing miR-124-3p may represent a novel therapeutic strategy for repetitive mild traumatic brain injury.

With the increase in the aging population, the occurrence of neurological disorders is rising. Recently, stem cell therapy has garnered attention due to its convenient sourcing, minimal invasiveness, and capacity for directed differentiation. However, there are some disadvantages, such as poor quality control, safety assessments, and ethical and logistical issues. Consequently, scientists have started to shift their attention from stem cells to extracellular vesicles due to their similar structures and properties. Beyond these parallels, extracellular vesicles can enhance biocompatibility, facilitate easy traversal of barriers, and minimize side effects. Furthermore, stem cell-derived extracellular vesicles can be engineered to load drugs and modify surfaces to enhance treatment outcomes. In this review, we summarize the functions of native stem cell-derived extracellular vesicles, subsequently review the strategies for the engineering of stem cell-derived extracellular vesicles and their applications in Alzheimer's disease, Parkinson's disease, and stroke, and discuss the challenges and solutions associated with the clinical translation of stem cell-derived extracellular vesicles.

Stem cells (SCs) have been used therapeutically for decades, yet their applications are limited by factors such as the risk of immune rejection and potential tumorigenicity. Extracellular vesicles (EVs), a key paracrine component of stem cell potency, overcome the drawbacks of stem cell applications as a cell-free therapeutic agent and play an important role in treating various diseases. However, EVs derived from two-dimensional (2D) planar culture of SCs have low yield and face challenges in large-scale production, which hinders the clinical translation of EVs. Three-dimensional (3D) culture, given its ability to more realistically simulate the in vivo environment, can not only expand SCs in large quantities, but also improve the yield and activity of EVs, changing the content of EVs and improving their therapeutic effects. In this review, we briefly describe the advantages of EVs and EV-related clinical applications, provide an overview of 3D cell culture, and finally focus on specific applications and future perspectives of EVs derived from 3D culture of different SCs.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by continuous and selective degeneration or death of dopamine neurons in the midbrain, leading to dysfunction of the nigrostriatal neural circuits. Current clinical treatments for PD include drug treatment and surgery, which provide short-term relief of symptoms but are associated with many side effects and cannot reverse the progression of PD. Pluripotent/multipotent stem cells possess a self-renewal capacity and the potential to differentiate into dopaminergic neurons. Transplantation of pluripotent/multipotent stem cells or dopaminergic neurons derived from these cells is a promising strategy for the complete repair of damaged neural circuits in PD. This article reviews and summarizes the current preclinical/clinical treatments for PD, their efficacies, and the advantages/disadvantages of various stem cells, including pluripotent and multipotent stem cells, to provide a detailed overview of how these cells can be applied in the treatment of PD, as well as the challenges and bottlenecks that need to be overcome in future translational studies.

Advances in stem cell (SC) technology allow the generation of cellular models that recapitulate the histological, molecular and physiological properties of humanized in vitro three dimensional (3D) models, as well as production of cell-derived therapeutics such as extracellular vesicles (EVs). Improvements in organ-on-chip platforms and human induced pluripotent stem cells (hiPSCs) derived neural/glial cells provide unprecedented systems for studying 3D personalized neural tissue modeling with easy setup and fast output. Here, we highlight the key points in differentiation procedures for neurons, astrocytes, oligodendrocytes and microglia from single origin hiPSCs. Additionally, we present a well-defined humanized neural tissue-on-chip model composed of differentiated cells with the same genetic backgrounds, as well as the therapeutic potential of bone marrow mesenchymal stem cells (BMSCs)-derived extracellular vesicles to propose a novel treatment for neuroinflammation derived diseases. Around 100 nm CD9 + EVs promote a more anti-inflammatory and pro-remodeling of cell-cell interaction cytokine responses on tumor necrosis factor-α (TNF-α) induced neuroinflammation in neural tissue-on-chip model which is ideal for modeling authentic neural-glial patho-physiology.

The NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome is a multimeric protein complex that is engaged in the innate immune system and plays a vital role in inflammatory reactions. Activation of the NLRP3 inflammasome and subsequent release of proinflammatory cytokines can be triggered by microbial infection or cellular injury. The NLRP3 inflammasome has been implicated in the pathogenesis of many disorders affecting the central nervous system (CNS), ranging from stroke, traumatic brain injury, and spinal cord injury to Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, and depression. Furthermore, emerging evidence has suggested that mesenchymal stem cells (MSCs) and their exosomes may modulate NLRP3 inflammasome activation in a way that might be promising for the therapeutic management of CNS diseases. In the present review, particular focus is placed on highlighting and discussing recent scientific evidence regarding the regulatory effects of MSC-based therapies on the NLRP3 inflammasome activation and their potential to counteract proinflammatory responses and pyroptotic cell death in the CNS, thereby achieving neuroprotective impacts and improvement in behavioral impairments.