Spinal cord injury (SCI) is a devastating event for the central nervous system (CNS), often resulting in the loss of sensory and motor functions. It profoundly affects both the physiological and psychological well-being of patients, reducing their quality of life while also imposing significant economic pressure on families and the healthcare system. Due to the complex pathophysiology of SCI, effective treatments for promoting recovery remain scarce. Mesenchymal stem cell-derived exosomes (MSC-Exos) offer advantages such as low immunogenicity, good biocompatibility, and the ability to cross the blood-spinal cord barrier (BSCB). In preclinical studies, they have progressively shown efficacy in promoting SCI repair and functional recovery. However, the low yield and insufficient targeting of MSC-Exos limit their therapeutic efficacy. Currently, genetic engineering and other preprocessing techniques are being employed to optimize both the yield and functional properties of exosomes, thereby enhancing their therapeutic potential. Therefore, this paper provides an overview of the pathophysiology of SCI and the biogenesis of exosomes. It also summarizes current approaches to optimizing exosome performance. Additionally, it details the mechanisms through which optimized exosomes provide neuroprotection and explores the potential of combined treatments involving MSC-Exos and hydrogels.

The aim of this study is to investigate the impact and mechanism of action of exosomes derived from bone marrow mesenchymal stem cells (BMSCs) in the treatment of heart failure (HF).

The analysis of gene sequencing data set was employed to identify potential therapeutic target proteins for HF. Subsequently, H9C2 cells and Sprague-Dawley (SD) rats were utilized as experimental models to simulate doxorubicin hydrochloride (Doxorubicin, Dox)-induced myocardial injury. This approach was employed to investigate the expression changes of inflammatory factors, including TNF-α, IL-6, IL-1β, sST2, and Gal-3, as well as the alterations in their expression following exosome treatment. Meanwhile, the mechanism of exosomes in relieving HF and inhibiting inflammation were investigated using constructed KLF 4 knockout cell lines and SD rats.

BMSC-derived exosomes were capable of enhancing the expression level of KLF4 in cardiomyocytes, decreasing the expression levels of myocardial damage markers BNP and hs-TnI, as well as inflammatory factors TNF-α, IL-6, IL-1β, sST2, and Gal-3, thereby alleviating HF injury. In vitro and in vivo experiments have shown that exosomal treatment decreases the expression of BNP and hs-TnI, which are indicators of myocardial injury, along with the release of inflammatory cytokines in cardiomyocytes. Concurrently, the expression of KLF4 was downregulated, leading to a significant reduction in this physiological modulation.

BMSC-derived exosomes exhibit superior therapeutic potential for HF by enhancing the expression of KLF4 and mitigating inflammation in myocardial tissue.

Bone-related diseases impact a large portion of the global population and, due to their high disability rates and limited treatment options, pose significant medical and economic challenges. Mesenchymal stem cells (MSCs) can differentiate into multiple cell types and offer strong regenerative potential, making them promising for treating various diseases. However, issues with the immune response and cell survival limit the effectiveness of cell transplantation. This has led to increased interest in cell-free stem cell therapy, particularly the use of exosomes, which is the most studied form of this approach. Exosomes are extracellular vesicles that contain proteins, lipids, and nucleic acids and play a key role in cell communication and material exchange. Pyroptosis, a form of cell death involved in innate immunity, is also associated with many diseases. Studies have shown that MSC-derived exosomes have therapeutic potential for treating a range of conditions by regulating inflammation and pyroptosis. This study explored the role of MSC-derived exosomes in modulating pyroptosis to improve the treatment of bone-related diseases.

Recently, a growing focus has been on identifying critical mechanisms in neurological diseases that trigger a cascade of events, making it easier to target them effectively. One such mechanism is the inflammasome, an essential component of the immune response system that plays a crucial role in disease progression. The NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 3) inflammasome is a subcellular multiprotein complex that is widely expressed in the central nervous system (CNS) and can be activated by a variety of external and internal stimuli. When activated, the NLRP3 inflammasome triggers the production of proinflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18) and facilitates rapid cell death by assembling the inflammasome. These cytokines initiate inflammatory responses through various downstream signaling pathways, leading to damage to neurons. Therefore, the NLRP3 inflammasome is considered a significant contributor to the development of neuroinflammation. To counter the damage caused by NLRP3 inflammasome activation, researchers have investigated various interventions such as small molecules, antibodies, and cellular and gene therapy to regulate inflammasome activity. For instance, recent studies indicate that substances like micro-RNAs (e.g., miR-29c and mR-190) and drugs such as melatonin can reduce neuronal damage and suppress neuroinflammation through NLRP3. Furthermore, the transplantation of bone marrow mesenchymal stem cells resulted in a significant reduction in the levels of pyroptosis-related proteins NLRP3, caspase-1, IL-1β, and IL-18. However, it would benefit future research to have an in-depth review of the pharmacological and biological interventions targeting inflammasome activity. Therefore, our review of current evidence demonstrates that targeting NLRP3 inflammasomes could be a pivotal approach for intervention in neurological disorders.

Spinal cord injury (SCI) is a common clinical condition of the central nervous system that can lead to sensory and motor impairment below the injury level or permanent loss of function in severe cases. Dynamic spatiotemporal neuroinflammation is vital to neurological recovery, which is collectively constituted by the dynamic changes in a series of inflammatory cells, including microglia, neutrophils, and astrocytes, among others. Immunomodulatory nanomaterials can readily improve the therapeutic effects and simultaneously overcome various drawbacks associated with treatment, such as the off-target side effects and loss of bioactivity of immune agents during circulation. In this review, we discuss the role of dynamic spatiotemporal inflammation in secondary injuries after SCI, elaborate on the mechanism of action and effect of existing nanomaterials in treating SCI, and summarize the mechanism(s) whereby they regulate inflammation. Finally, the challenges and prospects associated with using nanotechnology to modulate immunotherapy are discussed to provide new insights for future treatment. Deciphering the intricate spatiotemporal mechanisms of neuroinflammation in SCI requires further in-depth studies. Therefore, SCI continues to represent a formidable challenge.

Stem-cell derived extracellular vesicles (EVs) have shown promise in preclinical spinal cord injury (SCI) models but lack a comprehensive literature review for clinical translation guidance.

This meta-analysis with trial sequential analysis systematically search PubMed, Web of Science, Embase, and Cochrane Library databases. Prespecified inclusion criteria were studies reporting on measurable outcomes relevant to SCI repair. Risk of bias and quality of reporting were assessed. Random-effects meta-analyses and subgroup analyses comparing natural and bio-engineered EVs were performed. The study was registered with PROSPERO (CRD42024512122).

The search identified 3935 records, of which 39 studies were included, totaling 1801 animals. Administration of EVs significantly improved locomotor function as measured by Basso-Beattie-Bresnahan or Basso-Mouse-Scale scores at 1 week (natural EVs: SMD 1.50, 95 % CI 1.06-1.95; bio-engineered EVs: SMD 1.93, 95 % CI 1.34-2.52) and 3 weeks (natural EVs: SMD 2.57, 95 % CI 1.96-3.17; bio-engineered EVs: SMD 3.16, 95 % CI 2.29-4.02) post-injury. Subgroup analyses indicated surface modification approaches were most effective among bio-engineered EV strategies. EVs also promoted nerve growth (SMD 2.95, 95 % CI 2.12-3.78), enhanced neuron conductivity (MD 0.75, 95 %CI 0.59-0.90), alleviated inflammation (SMD -3.12, 95 % CI -4.15--2.10), and reduced lesion size (SMD -2.90, 95 % CI -3.87--1.93).

Both natural and bio-engineered EVs improve functional and pathological outcomes in animal models of SCI. The enhanced benefits observed with bio-engineered EVs, particularly those utilizing surface modification approaches, highlight the importance of continued exploration into bio-engineering techniques to optimize EVs' therapeutic efficacy for SCI repair. Protocol Registration CRD42024512122.

Neurological disorders are being increasingly recognized as major causes of death and disability around the world. Neurological disorders refer to a broad range of medical conditions that affect the brain and spinal cord. These disorders can have various causes, including genetic factors, infections, trauma, autoimmune reactions, or neurodegenerative processes. Each disorder has its own unique symptoms, progression, and treatment options. Optimal communication between interneurons and neuron-glia cells within the homeostatic microenvironment is of paramount importance. Within this microenvironment, exosomes play a significant role in promoting intercellular communication by transferring a diverse cargo of contents, including proteins, lipids, and non-coding RNAs (ncRNAs). Partially, nervous system homeostasis is preserved by various stem cell-derived exosomal ncRNAs, which include circular RNAs (circRNAs), long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and PIWI-interacting RNAs (piRNAs). The diversity of these exosomal ncRNAs suggests their potential to influence multiple pathways and cellular processes within the nervous system. Stem cell-derived exosomes and their ncRNA contents have been investigated for potential therapeutic uses in neurological disorders, owing to their demonstrated capabilities in neuroprotection, neuroregeneration, and modulation of disease-related pathways. The ability of stem cell-derived exosomes to cross the blood-brain barrier makes them a promising delivery vehicle for therapeutic ncRNAs. This review aims to summarize the current understanding of different stem cell-derived exosomal ncRNAs and their therapeutic potential and clinical applications.

Spinal cord injury (SCI) results in significant neural damage and inhibition of axonal regeneration due to an imbalanced microenvironment. Extensive evidence supports the efficacy of mesenchymal stem cell (MSC) transplantation as a therapeutic approach for SCI. This review aims to present an overview of MSC regulation on the imbalanced microenvironment following SCI, specifically focusing on inflammation, neurotrophy and axonal regeneration. The application, limitations and future prospects of MSC transplantation are discussed as well. Generally, a comprehensive perspective is provided for the clinical translation of MSC transplantation for SCI.

Pyroptosis, a lytic and pro-inflammatory cell death, is important in various pathophysiological processes. Host- and bacteria-derived extracellular vesicles (EVs), as natural nanocarriers messengers, are versatile mediators of intercellular communication between different types of cells. Recently, emerging research has suggested that EVs exhibit multifaceted roles in disease progression by manipulating pyroptosis. This review focuses on new findings concerning how EVs shape disease progression in infectious and non-infectious diseases by regulating pyroptosis. Understanding the characteristics and activity of EVs-mediated pyroptotic death may conducive to the discovery of novel mechanisms and more efficient therapeutic targets in infectious and non-infectious diseases.

Spinal cord injury (SCI) is a highly debilitating disorder of the central nervous system that can severely impact an affected patient's quality of life. This study aimed to examine how adipose-derived mesenchymal stem cell exosomes (ADSC-exos) can be used to treat spinal cord injury. We analysed differentially expressed mRNAs in SCI using bioinformatics data, gene expression profiles in inflammatory cell models, RT-qPCR and WB. Apoptosis was detected with flow cytometry. Starbase provides the control mechanism for FDFT1. Target interactions were detected with dual-luciferase reporter and RIP assays. Exosomes were isolated from adipose tissue-derived mesenchymal stem cells and subsequently characterized with western blot analysis, transmission electron microscopy and nanoparticle tracking analysis. By analysing the GSE102964 database, we found that FDFT1 was significantly downregulated as SCI progressed. Overexpression of FDFT1 can significantly reverse the inflammatory response and apoptosis of BV2 cells induced by hemin. Mechanically, ADSC-exos can affect the expression of FDFT1 through the ceRNA mechanism mediated by LRRC75A-AS1 and in an RBP-dependent manner mediated by IGF2BP2. The overexpression of LRRC75A-AS1 significantly enhances BV2 apoptosis and can be reversed by FDFT1 knockdown. ADSC-exos LRRC75A-AS1 inhibits inflammation and reduces SCI by increasing the expression and stability of FDFT1 mRNA in a ceRNA and RBP-dependent manner.

Central nervous system injuries have a high rate of resulting in disability and mortality; however, at present, effective treatments are lacking. Programmed cell death, which is a genetically determined form of active and ordered cell death with many types, has recently attracted increasing attention due to its functions in determining the fate of cell survival. A growing number of studies have suggested that programmed cell death is involved in central nervous system injuries and plays an important role in the progression of brain damage. In this review, we provide an overview of the role of programmed cell death in central nervous system injuries, including the pathways involved in mitophagy, pyroptosis, ferroptosis, and necroptosis, and the underlying mechanisms by which mitophagy regulates pyroptosis, ferroptosis, and necroptosis. We also discuss the new direction of therapeutic strategies targeting mitophagy for the treatment of central nervous system injuries, with the aim to determine the connection between programmed cell death and central nervous system injuries and to identify new therapies to modulate programmed cell death following central nervous system injury. In conclusion, based on these properties and effects, interventions targeting programmed cell death could be developed as potential therapeutic agents for central nervous system injury patients.

Nerve injuries significantly impact the quality of life for patients, with severe cases posing life-threatening risks. A comprehensive understanding of the pathophysiological mechanisms underlying nerve injury is crucial to the development of effective strategies to promote nerve regeneration. Circular RNAs (circRNAs), a recently characterized class of RNAs distinguished by their covalently closed-loop structures, have been shown to play an important role in various biological processes. Numerous studies have highlighted the pivotal role of circRNAs in nerve regeneration, identifying them as potential therapeutic targets. This review aims to succinctly outline the latest advances in the role of circRNAs related to nerve injury repair and the underlying mechanisms, including peripheral nerve injury, traumatic brain injury, spinal cord injury, and neuropathic pain. Finally, we discuss the potential applications of circRNAs in drug development and consider the potential directions for future research in this field to provide insights into circRNAs in nerve injury repair.

Mesenchymal stem cells (MSCs) are widely distributed pluripotent stem cells with powerful immunomodulatory capacity. MSCs transplantation therapy (MSCT) is widely used in the fields of tissue regeneration and repair, and treatment of inflammatory diseases. Apoptosis is an important way for tissues to maintain cell renewal, but it also plays an important role in various diseases. And many studies have shown that MSCs improves the diseases by regulating cell apoptosis. The regulation of MSCs on apoptosis is double-sided. On the one hand, MSCs significantly inhibit the apoptosis of diseased cells. On the other hand, MSCs also promote the apoptosis of tumor cells and excessive immune cells. Furthermore, MSCs regulate apoptosis through multiple molecules and pathways, including three classical apoptotic signaling pathways and other pathways. In this review, we summarize the current evidence on the regulation of apoptosis by MSCs.

Osteoporosis is a chronic disease that seriously affects the quality of life and longevity of the elderly, so exploring the mechanism of osteoporosis is crucial for drug development and treatment. Bone marrow mesenchymal stem cells are stem cells with multiple differentiation potentials in bone marrow, and changing their differentiation direction can change bone mass. As an extracellular superoxide dismutase, Superoxide Dismutase 3 (SOD3) has been proved to play an important role in multiple organs, but the detailed mechanism of action in bone metabolism is still unclear. In this study, the results of clinical serum samples ELISA and single cell sequencing chip analysis proved that the expression of SOD3 was positively correlated with bone mass, and SOD3 was mainly expressed in osteoblasts and adipocytes and rarely expressed in osteoblasts in BMSCs. In vitro experiments showed that SOD3 can promote osteogenesis and inhibit adipogenesis. Compared with WT mice, the mice that were knocked out of SOD3 had a significant decrease in bone mineral density and significant changes in related parameters. The results of HE and IHC staining suggested that knocking out SOD3 would lead to fat accumulation in the bone marrow cavity and weakened osteogenesis. Both in vitro and in vivo experiments indicated that SOD3 affects bone metabolism by promoting osteogenesis and inhibiting adipogenesis. The results of transcriptome sequencing and revalidation showed that SOD3 can affect the expression of FLT1. Through in vitro experiments, we proved that FLT1 can also promote osteogenesis and inhibit adipogenesis. In addition, through the repeated experiments, the interaction between the two molecules (SOD3 and FLT1) was verified again. Finally, it was verified by WB that SOD3 regulates FLT1 to affect bone metabolism through PI3K/AKT and MAPK pathways.

Ulcerative colitis (UC) is a chronic recurrent inflammatory bowel disease. Despite ongoing advances in our understanding of UC, its pathogenesis is yet unelucidated, underscoring the urgent need for novel treatment strategies for patients with UC. Exosomes are nanoscale membrane particles that mediate intercellular communication by carrying various bioactive molecules, such as proteins, RNAs, DNA, and metabolites. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a cytosolic tripartite protein complex whose activation induces the maturation and secretion of proinflammatory cytokines interleukin-1β (IL-1β) and IL-18, triggering the inflammatory response to a pathogenic agent or injury. Growing evidence suggests that exosomes are new modulators of the NLRP3 inflammasome, with vital roles in the pathological process of UC. Here, recent evidence is reviewed on the role of exosomes and NLRP3 inflammasome in UC. First, the dual role of exosomes on NLRP3 inflammasome and the effect of NLRP3 inflammasome on exosome secretion are summarized. Finally, an outlook on the directions of exosome-NLRP3 inflammasome crosstalk research in the context of UC is proposed and areas of further research on this topic are highlighted.

Hepatic ischemia-reperfusion injury (HIRI) is a complication of hepatectomy that affects the functional recovery of the remnant liver, which has been demonstrated to be associated with pyroptosis and apoptosis. Mesenchymal stem cells (MSCs) can protect against HIRI in rodents. Paracrine mechanisms of MSCs indicated that MSCs-derived exosomes (MSCs-exo) are one of the important components within the paracrine substances of MSCs. Moreover, miniature pigs are ideal experimental animals in comparative medicine compared to rodents. Accordingly, this study aimed to investigate whether hepatectomy combined with HIRI in miniature pigs would induce pyroptosis and whether adipose-derived MSCs (ADSCs) and their exosomes (ADSCs-exo) could positively mitigate apoptosis and pyroptosis. The study also compared the differences in the effects and the role of ADSCs and ADSCs-exo in pyroptosis and apoptosis. Results showed that severe ultrastructure damage occurred in liver tissues and systemic inflammatory response was induced after surgery, with TLR4/MyD88/NFκB/HMGB1 activation, NLRP3-ASC-Caspase1 complex generation, GSDMD revitalization, and IL-1β, IL-18, and LDH elevation in the serum. Furthermore, expression of Fas-Fasl-Caspase8 and CytC-APAF1-Caspase9 was increased in the liver. The ADSCs or ADSCs-exo intervention could inhibit the expression of these indicators and improve the ultrastructural pathological changes and systemic inflammatory response. There was no significant difference between the two intervention groups. In summary, ADSCs-exo could effectively inhibit pyroptosis and apoptosis similar to ADSCs and may be considered a safe and effective cell-free therapy to protect against liver injury.

Ischemic cardiomyopathy is treated mainly with thrombolytic drugs, percutaneous coronary intervention, and coronary artery bypass grafting to recanalize blocked vessels. Myocardial ischemia-reperfusion injury (MIRI) is an unavoidable complication of obstructive revascularization. Compared with those of myocardial ischemic injury, few effective therapeutic options are available for MIRI treatment. The pathophysiological mechanisms of MIRI involve the inflammatory response, the immune response, oxidative stress, apoptosis, intracellular Ca2+ overload, and cardiomyocyte energy metabolism. These mechanisms exacerbate MIRI. Mesenchymal stem cell-derived exosomes (MSC-EXOs) can alleviate MIRI through these mechanisms and, to some extent, prevent the limitations caused by direct MSC administration. Therefore, using MSC-EXOs instead of MSCs to treat MIRI is a potentially beneficial cell-free treatment strategy. In this review, we describe the mechanism of action of MSC-EXO-derived noncoding RNAs in the treatment of MIRI and discuss the advantages and limitations of this strategy, as well as possible future research directions.

circACTA2 derived from the smooth muscle α-actin gene plays an important role in the regulation of vascular smooth muscle cell (VSMC) phenotype. The activation of NLRP3 inflammasome is involved in VSMC phenotypic switching. However, the mechanistic relationship between circACTA2 and NLRP3 inflammasome during vascular remodeling remains poorly understood. Here, we showed that circACTA2 was down-regulated in human intimal hyperplasia. circACTA2 overexpression in circACTA2 transgenic mice significantly decreased the neointimal hyperplasia induced by vascular injury, which is concomitant with a decrease in IL-18, IL-1β, TNF-α, and IL-6 levels. Gain- and loss-of-function studies revealed that circACTA2 alleviated VSMC inflammation by suppressing the activation of NLRP3 inflammasome. Mechanistically, circACTA2 inhibited the expression of NF-κB p65 and p50 subunits and interacted with p50, which impedes the formation of the p50/p65 heterodimer and nuclear translocation induced by TNF-α, thus resulting in the suppression of NLRP3 gene transcription and inflammasome activation. Furthermore, circACTA2 overexpression mitigated inflammation via repressing NLRP3 inflammasome-mediated VSMC pyroptosis. Importantly, employing a decoy oligonucleotide to compete with circACTA2 for binding to p50 could attenuate the expression of NLRP3, ASC, and caspase-1. These findings provide a novel insight into the functional roles of circACTA2 in VSMCs, and targeting the circACTA2-NF-κB-NLRP3 axis represents a promising therapeutic strategy for vascular remodeling.

Secondary chronic neuropathic pain (NP) in addition to sensory, motor, or autonomic dysfunction can significantly reduce quality of life after spinal cord injury (SCI). The mechanisms of SCI-related NP have been studied in clinical trials and with the use of experimental models. However, in developing new treatment strategies for SCI patients, NP poses new challenges. The inflammatory response following SCI promotes the development of NP. Previous studies suggest that reducing neuroinflammation following SCI can improve NP-related behaviors. Intensive studies of the roles of non-coding RNAs in SCI have discovered that ncRNAs bind target mRNA, act between activated glia, neuronal cells, or other immunocytes, regulate gene expression, inhibit inflammation, and influence the prognosis of NP.

Doxorubicin (DOX) can contribute to severe myocardial injury, and bone marrow stromal cells (BMSC)-exosomes (Exos) improves acute myocardial infarction. Hence, this research investigated whether BMSC-Exos alleviated DOX-induced myocardial injury.

BMSC-derived Exos were isolated and identified, and the optimal concentration of DOX was confirmed. H9C2 cells were treated with DOX and BMSC-Exos or in combination with the protein kinase B (AKT) inhibitor. Reactive oxygen species (ROS) and JC-1 were detected to assess oxidative stress (OS) and mitochondrial membrane damage, respectively. In addition, the expression of pyroptosis-related molecules was measured. The expression of phosphatidylinositol 3 kinase (PI3K)-AKT pathway-related proteins and the phosphorylation and acetylation of forkhead box O1 (Foxo1) in the cell nucleus and cytoplasm were tested. Last, interactions between Foxo1 and gasdermin D (GSDMD) were assessed.

BMSC-Exo treatment increased viability and mitochondrial membrane potential and reduced lactic dehydrogenase release and ROS levels in DOX-treated H9C2 cells. Furthermore, the addition of BMSC-Exos suppressed DOX-induced activation and upregulation of NLRP3 and apoptosis-associated speck-like protein containing A CARD (ASC) and in vitro cleavage of caspase-1, GSDMD, interleukin (IL)-1β, and IL-18 proteins. Additionally, BMSC-Exo treatment enhanced the expression of phosphorylated (p)-PI3K, p-AKT, and p-mTOR in DOX-treated H9C2 cells and the levels of phosphorylated Foxo1 in the cytoplasm of DOX-treated H9C2 cells. Foxo1 was enriched in the promoter region of GSDMD. Moreover, the AKT inhibitor API-2 annulled the effects of BMSC-Exos on OS, pyroptosis, and Foxo1 phosphorylation in DOX-treated H9C2 cells.

BMSC-Exos phosphorylated Foxo1 and inactivated Foxo1 transcription via the PI3K-AKT pathway to diminish GSDMD expression, thus restraining DOX-induced pyroptosis and OS of myocardial cells.

Exosome-based therapy is emerging as a promising strategy to promote bone regeneration due to exosomal bioactive cargos, among which circular RNA (circRNA) has recently been recognized as the key effector. The role of exosomal circRNA derived from bone marrow mesenchymal stem cells (BMSCs) has not been well-defined. The present study aimed to clarify the regulatory function and molecular mechanism of BMSC-derived exosomal circRNA in osteogenesis. Exosomes derived from bone marrow mesenchymal stem cells (BMSC-Exos) were isolated and identified. BMSC-Exos' pro-osteogenic effect on MC3T3-E1 cells was validated by alkaline phosphatase (ALP) activity and Alizarin Red staining. Through bioinformatic analysis and molecular experiments, circHIPK3 was selected and verified as the key circRNA of BMSC-Exos to promote osteoblast differentiation of MC3T3-E1 cells. Mechanistically, circHIPK3 acted as an miR-29a-5p sponge and functioned in mitophagy via targeting miR-29a-5p and PINK1. Additionally, we showed that the mitophagy level of MC3T3-E1 cells were mediated by BMSC-Exos, which promoted the osteogenic differentiation. Collectively, our results revealed an important role for BMSC-derived exosomal circHIPK3 in osteogenesis. These findings provide a potentially effective therapeutic strategy for bone regeneration.

Spinal cord injury (SCI) brings a heavy burden to individuals and society, and there is no effective treatment at present. Exosomes (EX) are cell secreted vesicles containing molecules such as nucleic acids and proteins, which hold promise for the treatment of SCI. Netrin-1 is an axon guidance factor that regulates neuronal growth. We investigated the effects of engineered EX enriched in netrin-1 chemically synthetic modified message RNA (modRNA) in treating SCI in an attempt to find a novel therapeutic approach for SCI.

Netrin-1 modRNA was transfected into bone marrow mesenchymal stem cells to obtain EX enriched with netrin-1 (EX-netrin1). We built an inflammatory model in vitro with lipopolysaccharide (LPS) in vitro to study the therapeutic effect of EX-netrin1 on SCI. For experiments in vitro, ELISA, CCK-8 assay, immunofluorescence staining, lactate dehydrogenase release experiments test, real-time quantitative polymerase chain reaction, and western blot were conducted. At the same time, we constructed a rat model of SCI. MRI, hematoxylin-eosin and Nissl staining were used to assess the extent of SCI in rats.

In vitro experiments showed that EX had no effect on the viability of oligodendrocytes and PC12 cells. EX-netrin1 could attenuate LPS-induced inflammation and pyroptosis and accelerate axonal/dentritic growth in PC12 cells/oligodendrocytes. In addition, netrin-1 could activate the PI3K/AKT/mTOR signalling pathway upon binding to its receptor unc5b. When Unc5b and PI3K were inhibited, the effect of EX-netrin1 was weakened, which could be reversed by PI3K or mTOR activator. Our in vivo experiments indicated that EX-netrin1 could promote recovery in rats with SCI.

We found that EX-netrin1 regulated inflammation, pyroptosis and axon growth in SCI via the Unc5b/PI3K/AKT/mTOR pathway, which provides a new strategy for the treatment of SCI.

Extracellular vesicles (EVs) including exosomes are vesicular vesicles with phospholipid bilayer implicated in many cellular interactions and have the ability to transfer multiple types of cargo to cells. It has been found that EVs can package various molecules including proteins and nucleic acids (DNA, mRNA, and noncoding RNA). The discovery of EVs as carriers of proteins and various forms of RNA, such as microRNAs (miRNA) and long noncoding RNAs (lncRNA), has raised great interest in the field of drug delivery. Despite the underlying mechanisms of neuropathic pain being unclear, it has been shown that uncontrolled glial cell activation and the neuroinflammation response to noxious stimulation are important in the emergence and maintenance of neuropathic pain. Many studies have demonstrated a role for noncoding RNAs in the pathogenesis of neuropathic pain and EVs may offer possibilities as carriers of noncoding RNAs for potential in neuropathic pain treatment. In this article, the origins and clinical application of EVs and the mechanism of neuropathic pain development are briefly introduced. Furthermore, we demonstrate the therapeutic roles of EVs in neuropathic pain and that this involve vesicular regulation of glial cell activation and neuroinflammation.

Spinal Cord Injury (SCI) is a common neurological disorder with devastating psychical and psychosocial sequelae. The majority of patients after SCI suffer from permanent disability caused by motor dysfunction, impaired sensation, neuropathic pain, spasticity as well as urinary complications, and a small number of patients experience a complete recovery. Current standard treatment modalities of the SCI aim to prevent secondary injury and provide limited recovery of lost neurological functions. Stem Cell Therapy (SCT) represents an emerging treatment approach using the differentiation, paracrine, and self-renewal capabilities of stem cells to regenerate the injured spinal cord. To date, multipotent stem cells including mesenchymal stem cells (MSCs), neural stem cells (NSCs), and hematopoietic stem cells (HSCs) represent the most investigated types of stem cells for the treatment of SCI in preclinical and clinical studies. The microenvironment of SCI has a significant impact on the survival, proliferation, and differentiation of transplanted stem cells. Therefore, a deep understanding of the pathophysiology of SCI and molecular mechanisms through which stem cells act may help improve the treatment efficacy of SCT and find new therapeutic approaches such as stem-cell-derived exosomes, gene-modified stem cells, scaffolds, and nanomaterials. In this literature review, the pathogenesis of SCI and molecular mechanisms of action of multipotent stem cells including MSCs, NSCs, and HSCs are comprehensively described. Moreover, the clinical efficacy of multipotent stem cells in SCI treatment, an optimal protocol of stem cell administration, and recent therapeutic approaches based on or combined with SCT are also discussed.

Currently, bone defect repair is still an intractable clinical problem. Numerous treatments have been performed, but their clinical results are unsatisfactory. As a key element of cell-free therapy, exosome is becoming a promising tool of bone regeneration in recent decades, because of its promoting osteogenesis and osteogenic differentiation function in vivo and in vitro. However, low yield, weak activity, inefficient targeting ability, and unpredictable side effects of natural exosomes have limited the clinical application. To overcome the weakness, various approaches have been applied to produce engineering exosomes by regulating their production and function at present. In this review, we will focus on the engineering exosomes for bone defect repair. By summarizing the exosomal cargos affecting osteogenesis, the strategies of engineering exosomes and properties of exosome-integrated biomaterials, this work will provide novel insights into exploring advanced engineering exosome-based cell-free therapy for bone defect repair.

Spinal cord injury (SCI) often brings devastating consequences to patients and their families. Pathophysiologically, the primary insult causes irreversible damage to neurons and glial cells and initiates the secondary damage cascade, further leading to inflammation, ischemia, and cells death. In SCI, the release of various inflammatory mediators aggravates nerve injury. Pyroptosis is a new pro-inflammatory pattern of regulated cell death (RCD), mainly mediated by caspase-1 or caspase-11/4/5. Gasdermins family are pore-forming proteins known as the executor of pyroptosis and the gasdermin D (GSDMD) is best characterized. Pyroptosis occurs in multiple central nervous system (CNS) cell types, especially plays a vital role in the development of SCI. We review here the evidence for pyroptosis in SCI, and focus on the pyroptosis of different cells and the crosstalk between them. In addition, we discuss the interaction between pyroptosis and other forms of RCD in SCI. We also summarize the therapeutic strategies for pyroptosis inhibition, so as to provide novel ideas for improving outcomes following SCI.