JOURNAL/nrgr/04.03/01300535-202511000-00028/figure1/v/2024-12-20T164640Z/r/image-tiff Human neural stem cell-derived extracellular vesicles exhibit analogous functions to their parental cells, and can thus be used as substitutes for stem cells in stem cell therapy, thereby mitigating the risks of stem cell therapy and advancing the frontiers of stem cell-derived treatments. This lays a foundation for the development of potentially potent new treatment modalities for ischemic stroke. However, the precise mechanisms underlying the efficacy and safety of human neural stem cell-derived extracellular vesicles remain unclear, presenting challenges for clinical translation. To promote the translation of therapy based on human neural stem cell-derived extracellular vesicles from the bench to the bedside, we conducted a comprehensive preclinical study to evaluate the efficacy and safety of human neural stem cell-derived extracellular vesicles in the treatment of ischemic stroke. We found that administration of human neural stem cell-derived extracellular vesicles to an ischemic stroke rat model reduced the volume of cerebral infarction and promoted functional recovery by alleviating neuronal apoptosis. The human neural stem cell-derived extracellular vesicles reduced neuronal apoptosis by enhancing phosphorylation of phosphoinositide 3-kinase, mammalian target of rapamycin, and protein kinase B, and these effects were reversed by treatment with a phosphoinositide 3-kinase inhibitor. These findings suggest that human neural stem cell-derived extracellular vesicles play a neuroprotective role in ischemic stroke through activation of phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway. Finally, we showed that human neural stem cell-derived extracellular vesicles have a good in vivo safety profile. Therefore, human neural stem cell-derived extracellular vesicles are a promising potential agent for the treatment of ischemic stroke.

JOURNAL/nrgr/04.03/01300535-202508000-00024/figure1/v/2024-09-30T120553Z/r/image-tiff Patients with complete spinal cord injury retain the potential for volitional muscle activity in muscles located below the spinal injury level. However, because of prolonged inactivity, initial attempts to activate these muscles may not effectively engage any of the remaining neurons in the descending pathway. A previous study unexpectedly found that a brief clinical round of passive activity significantly increased volitional muscle activation, as measured by surface electromyography. In this study, we further explored the effect of passive activity on surface electromyographic signals during volitional control tasks among individuals with complete spinal cord injury. Eleven patients with chronic complete thoracic spinal cord injury were recruited. Surface electromyography data from eight major leg muscles were acquired and compared before and after the passive activity protocol. The results indicated that the passive activity led to an increased number of activated volitional muscles and an increased frequency of activation. Although the cumulative root mean square of surface electromyography amplitude for volitional control of movement showed a slight increase after passive activity, the difference was not statistically significant. These findings suggest that brief passive activity may enhance the ability to initiate volitional muscle activity during surface electromyography tasks and underscore the potential of passive activity for improving residual motor control among patients with motor complete spinal cord injury.

Spinal cord injury (SCI) represents a prevalent form of mechanical trauma, frequently resulting in significant disability and mortality. Uncoupling protein 2 (UCP2) has been recognized for its neuroprotective properties; however, its specific role in SCI remains to be elucidated. This study aims to investigate the neuroprotective effects of UCP2 in the context of SCI and to further explore its downstream mechanisms of action. Through in vitro experiments, we demonstrated that UCP2 overexpression significantly improved cell viability and inhibited apoptosis and inflammatory responses in the lipopolysaccharides (LPS)-induced SCI cell model. Results of animal experiments showed that adeno-associated virus-mediated overexpression of UCP2 contributed to the recovery of SCI-afflicted rats, evidenced by improved Basso, Beattie, and Bresnahan scores, decreased water content in spinal tissues, reduced number of apoptotic cells in spinal cord. Mechanistic investigations revealed that UCP2 directly interacts with annexin A1 (ANXA1), enhancing its protein stability through acetylation at the K58 site. Furthermore, UCP2 was found to activate the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway by upregulating ANXA1 expression. Rescue assays indicated that knockdown of ANXA1 or inactivation of the PI3K/AKT pathway by LY294002 treatment partially neutralized the protective effects of UCP2 overexpression against apoptosis and inflammatory responses in LPS-stimulated BV-2 cells. Taken together, this study concludes that UCP2 ameliorates apoptosis and inflammatory responses in the SCI model by modulating acetylation-mediated protein stabilization of ANXA1 and activating the PI3K/AKT pathway.

Severe spinal cord injury (SCI) represents a debilitating condition with long-term physical and socioeconomic impacts. Understanding the pathophysiology of SCI and therapeutic interventions such as decompressive laminectomy and expansive duraplasty is crucial for optimizing patient outcomes.

This systematic review explores the pathophysiology of SCI and evaluates evidence linking decompressive laminectomy and duraplasty to improved neuroplasticity and recovery.

A comprehensive search was conducted in PubMed, Web of Science, and Cochrane Library for studies on decompressive surgery in SCI. Inclusion criteria were original articles investigating pathophysiology, neuroplasticity mechanisms, or surgical outcomes. Data on pathophysiological changes, molecular markers, and functional outcomes were extracted.

From 1240 initial articles, 43 studies were included, encompassing both animal models and human clinical data. Findings highlighted the role of inflammatory cascades, blood-spinal cord barrier disruption, and neurotrophic factor modulation in recovery. Decompressive duraplasty was associated with improved intrathecal pressure (ITP) management and neuroplasticity markers, such as BDNF and GAP-43.

This review underscores the therapeutic potential of decompressive laminectomy and duraplasty in SCI. While evidence suggests benefits in promoting neuroplasticity, further research is needed to elucidate molecular mechanisms and refine interventions.

Traumatic brain injury (TBI) is a heterogeneous disease characterized by brain damage and functional impairment caused by external forces. Under the influence of multiple mechanisms, TBI can cause synaptic dysfunction, protein aggregation, mitochondrial dysfunction, oxidative stress, and neuroinflammatory cascade reactions, resulting in a high disability and mortality rate for patients and a heavy burden on families and society. Exosomes are cell-derived vesicles that encapsulate a variety of molecules, including proteins, lipids, mRNAs, and other small biomolecules. Among these, exosomes derived from mesenchymal stem cells (MSCs) have garnered significant attention owing to their therapeutic potential in the nervous system, offering broad clinical applicability. Recent studies have demonstrated that MSC-derived exosome injections in traumatic brain injury models effectively mitigate local inflammatory damage and promote nerve regeneration following injury. Owing to their small size, challenging replication, ease of preservation, and low immunogenicity, MSC exosomes are emerging as a promising therapeutic strategy for traumatic brain injury. This review explores the pathogenesis of traumatic brain injury, the underlying mechanisms of MSC exosome action, and the potential clinical applications of MSC exosomes in the treatment of traumatic brain injury.

Despite the lack of clinically validated strategies for treating spinal cord injury (SCI), combining therapeutic strategies with rehabilitation is believed to promote recovery of motor function; however, current research findings are inconsistent.

To explore whether combination therapy involving therapy and rehabilitative training (CIRT) has a synergistic effect on motor function recovery in animal models of SCI.

We conducted a systematic review and meta-analysis of studies identified in a keyword search of 6 databases and extracted open-field motor scores from the Basso Mouse Scale (BMS) and the Basso, Beattie, and Bresnahan Locomotor Rating Scale (BBB) for meta-analysis using a weighted mean difference (WMD) and 95 % CI. We also performed qualitative synthesis and analysis of secondary outcome measures related to histological improvements and adverse effects.

Eighty-seven preclinical studies were included. Combination treatment with treadmill training resulted in a significant improvement in motor function (1.40, 95 % CI 0.82 to 1.98, P < 0.01, I2 = 49 %), especially when initiated 1-2 weeks post-injury (1.77, 95 % CI 1.10 to 2.45, P < 0.01, I2 = 33 %) in rats. In mice, CIRT lasting <6 weeks may enhance recovery (0.95, 95 % CI 0.49 to 1.40, P < 0.01, I2 = 33 %). Although there is a trend toward better outcomes in the chronic phase, insufficient sample sizes prevent definitive conclusions from being drawn. Combined therapy also enhances the reorganization of inhibitory synaptic structures and functions, without aggravating allodynia or spasticity.

This systematic review and meta-analysis suggest that CIRT can lead to superior motor function recovery compared to single-modality therapy (SMT) in animal models of SCI, with no significant adverse effects on allodynia or spasticity. However, the efficacy of CIRT depends on various factors, and further research is needed to establish optimal treatment strategies and understand the underlying mechanisms of recovery.

After spinal cord injury (SCI), reactive astrocytes in the injured area are triggered after spinal cord injury (SCI) and to polarize into A1 astrocytes with a proinflammatory phenotype or A2 astrocytes with an anti-inflammatory phenotype. Monopolar spindle binder 2 (MOB2) induces astrocyte stellation, maintains cell homeostasis, and promotes neurite outgrowth; however, its role in the phenotypic transformation of reactive astrocytes remains unclear. Here, we confirmed for the first time that MOB2 is associated with A1/A2 phenotypic switching in reactive astrocytes following SCI in mice. MOB2 modulated A1/A2 transformation in a primary astrocyte reactive cell model. Therefore, we constructed MOB2 conditional knockout mice (MOB2GFAP-CKO) and discovered that conditional knockout of MOB2 inhibited the conversion of reactive astrocytes from A1 to A2 and hindered spinal cord function recovery. Mechanistically, MOB2 increased the activation of PI3K-AKT signaling to promote A1/A2 transformation in vitro, whereas sc79 (an AKT activator) reversed the subtype transformation of reactive astrocytes and improved functional recovery in MOB2GFAP-CKO mice after SCI. Taken together, study provides the first insights into how MOB2 acts as a novel regulator to promote the conversion this of the reactive astrocyte phenotype from A1 to A2, showing great potential for the treatment of SCI.

Uterine injury can cause uterine scarring, leading to a series of complications that threaten women's health. Uterine healing is a complex process, and there are currently no effective treatments. Although our previous studies have shown that bone marrow mesenchymal stem cells (BMSCs) promote uterine damage repair, the underlying mechanisms remain unclear. However, exploring the specific regulatory roles of BMSCs in uterine injury treatment is crucial for further understanding their functions and enhancing therapeutic efficacy.

To investigate the underlying mechanism by which BMSCs promote the process of uterine healing.

In in vivo experiments, we established a model of full-thickness uterine injury and injected BMSCs into the uterine wound. Transcriptome sequencing was performed to determine the enrichment of differentially expressed genes at the wound site. In in vitro experiments, we isolated rat uterine smooth muscle cells (USMCs) and cocultured them with BMSCs to observe the interaction between BMSCs and USMCs in the microenvironment.

We found that the differentially expressed genes were mainly related to cell growth, tissue repair, and angiogenesis, while the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway was highly enriched. Quantitative reverse-transcription polymerase chain reaction was used to validate differentially expressed genes, and the results demonstrated that BMSCs can upregulate genes related to regeneration and downregulate genes related to inflammation. Coculturing BMSCs promoted the migration and proliferation of USMCs, and the USMC microenvironment promoted the myogenic differentiation of BMSCs. Finally, we validated the PI3K/AKT pathway in tissues and cells and showed that BMSCs activate the PI3K/AKT pathway to promote the regeneration of uterine smooth muscle both in vivo and in vitro.

BMSCs upregulated uterine wound regeneration and anti-inflammatory factors and enhanced uterine smooth muscle proliferation through the PI3K/AKT pathway both in vivo and in vitro.

Spinal cord injury (SCI) is a severe disabling injury of the central nervous system that can lead to motor, sensory, and autonomic dysfunction below the level of the injury. According to its pathophysiological process, SCI can be divided into primary injury and secondary injury. Currently, multiple therapeutic strategies have been proposed to alleviate secondary injury and overcome the occurrence of neurodegenerative events. Although current treatment modalities have achieved varying degrees of success, they cannot effectively intervene or treat its pathological processes, which may be due to the complex treatment and protection mechanisms involved. Research has confirmed that signaling pathways play a crucial role in the pathological processes of SCI and the mechanisms of neuronal recovery. Mitogen-activated protein kinase (MAPK) signaling pathway plays a crucial role in neuronal differentiation, growth, survival and axon regeneration after central nervous system injury. Meanwhile, the MAPK signaling pathway is an important pathway closely related to the pathological processes of SCI. The MAPK signaling pathway is abnormally activated after SCI, and inhibiting the activity of MAPK pathway can effectively inhibit inflammation, oxidative stress, pain and apoptosis to promote the recovery of nerve function after SCI. Based on the role of the MAPK pathway in SCI, it may be a potential therapeutic target. This article summarizes the role and mechanism of MAPK pathway in SCI, and discusses the shortcomings and shortcomings of MAPK pathway in SCI field, as well as the potential challenges of targeting MAPK pathway in SCI treatment strategies. This article aims to elucidate the mechanism of the MAPK pathway in SCI to emphasize the role of targeting the MAPK pathway in the treatment of SCI, providing a theoretical basis for the MAPK pathway as a potential therapeutic target for SCI treatment.

Experimental study utilizing with a standardized model (MASCIS Impactor) of Spinal Cord Injury (SCI) in Balb C mouse model with implantation of mononuclear stem cells derived from the human umbilical cord and placenta blood in the early chronic phase of SCI.

The aim of this study was to evaluate the nerve regeneration and motor functional recovery in Balb C mice with surgically induced paraplegia in response to the use of mononuclear stem cells, in early chronic phase (> 2 weeks and < 6 months), because there is yet potential of neuronal and functional recovery as the neuronal scar is not still completely established.

Forty-eight mice were randomly assigned to 6 groups of 8 animals. Group 1 received the stem cells 3 weeks after the trauma, and Group 2 received them six weeks later. In Group 3, saline solution was injected at the site of the lesion 3 weeks after the trauma, and in Group 4, 6 weeks later. Group 5 underwent only spinal cord injury and Group 6 underwent laminectomy only. The scales used for motor assessment were BMS and MFS for 12 weeks.

The intervention groups showed statistically significant motor improvement. In the histopathological analysis, the intervention groups had a lower degree of injury (p < 0.05). Regarding axonal budding, the intervention groups showed increasing in axonal budding in the caudal portion (p < 0.05).

The use of stem cells in mice in the chronic phase after 3 and 6 weeks of SCI brings functional and histopathological benefits to them.

Mesenchymal stem cells (MSCs) have demonstrated considerable potential in tissue repair and the treatment of immune-related diseases, but there are problems with homing efficiency during MSCs transplantation. Exercise, as an intervention, has been shown to have an important impact on the properties of MSCs. This review summarizes the effects of exercise on the properties (including proliferation, apoptosis, differentiation, and homing) of bone marrow-derived MSCs and adipose-derived MSCs. Studies indicated that exercise enhances bone marrow-derived MSCs proliferation, osteogenic differentiation, and homing while reducing adipogenic differentiation. For adipose-derived MSCs, exercise enhances proliferation and reduces adipogenic differentiation. In addition, studies have investigated the therapeutic effects of combined therapy of MSCs transplantation with exercise on diseases of the bone, cardiac, and nervous systems. The combined therapy improves tissue repair by increasing the homing of transplanted MSCs and cytokine secretion (such as neurotrophin 4). Furthermore, MSCs transplantation also has potential for the treatment of obesity. Although the effect is not significant in weight loss, MSCs transplantation shows effects in controlling blood glucose, improving dyslipidemia, reducing inflammation, and improving liver disease. Finally, the potential role of combined MSCs transplantation and exercise therapy in addressing obesity is discussed.

This study aimed to assess the impact of conditioned medium from epidermal neural crest stem cells (EPI-NCSCs-CM) on functional recovery following spinal cord injury (SCI), while also exploring the involvement of the PI3K-AKT signaling pathway in regulating neuronal apoptosis. EPI-NCSCs were isolated from 10-day-old Sprague-Dawley rats and cultured for 48 h to obtain EPI-NCSC-CM. SHSY-5Y cells were subjected with H2O2 treatment to induce apoptosis. Cell viability and survival rates were evaluated using the CCK-8 assay and calcein-AM/PI staining. SCI contusion model was established in adult Sprague-Dawley rats to assess functional recovery, utilizing the Basso, Beattie and Bresnahan (BBB) scoring system, inclined test, and footprint observation. Neurological restoration after SCI was analyzed through electrophysiological recordings. Histological analysis included hematoxylin and eosin (H&E) staining and Nissl staining to evaluate tissue organization. Apoptosis and oxidative stress levels were assessed using TUNEL staining and ROS detection methods. Additionally, western blotting was performed to examine the expression of apoptotic markers and proteins related to the PI3K/AKT signaling pathway. EPI-NCSC-CM significantly facilitated functional and histological recovery in SCI rats by inhibiting neuronal apoptosis through modulation of the PI3K/AKT pathway. Administration of EPI-NCSCs-CM alleviated H2O2-induced neurotoxicity in SHSY-5Y cells in vitro. The use of LY294002, a PI3K inhibitor, underscored the crucial role of the PI3K/AKT signaling pathway in regulating neuronal apoptosis. This study contributes to the ongoing exploration of molecular pathways involved in spinal cord injury (SCI) repair, focusing on the therapeutic potential of EPI-NCSC-CM. The research findings indicate that EPI-NCSC-CM exerts a neuroprotective effect by suppressing neuronal apoptosis through activation of the PI3K/AKT pathway in SCI rats. These results highlight the promising role of EPI-NCSC-CM as a potential treatment strategy for SCI, emphasizing the significance of the PI3K/AKT pathway in mediating its beneficial effects.

Spinal cord injury (SCI) is a severe disabling disease that is characterized by inflammation and oxidative reactions. Tangeretin has been shown to possess significant antioxidant and anti-inflammatory activities. The Keap1/Nrf2 pathway, downstream of the Sesn2 gene, is involved in regulating the inflammation and oxidative response. The main objective of this study was to investigate the effect of tangeretin on SCI and its possible mechanism through cell and animal models. A T9 clamp injury was used for the mouse model and the LPS-induced stimulation of BV-2 cells was used for the cell model. The improvement of motor function after SCI was assessed by open field, swimming, and footprint experiments. The morphological characteristics of mouse spinal cord tissue and the levels of INOS, Sesn2, TNF-α, Keap1, Nrf2, IL-10, and reactive oxygen species (ROS) in vivo and in vitro were measured by several methods including western blotting, qPCR, immunofluorescence, HE, and Nissl staining. In vivo data showed that tangeretin can improve motor function recovery and reduce neuron loss and injury size in mice with SCI. Simultaneously, the in vitro findings suggested that treatment of BV-2 cells with tangeretin after LPS stimulation reduced the production of inflammatory factors and ROS, and could convert BV-2 cells from the M1 to the M2 type. Furthermore, Sesn2 knockout suppressed Keap1/Nrf2, inflammatory factors, ROS levels, and the M1 to M2 transition. Tangeretin can alleviate the inflammation and oxidative response induced by SCI by activating the Sesn2/Keap1/Nrf2 pathway.

Spinal cord injury is considered one of the most difficult injuries to repair and has one of the worst prognoses for injuries to the nervous system. Following surgery, the poor regenerative capacity of nerve cells and the generation of new scars can make it very difficult for the impaired nervous system to restore its neural functionality. Traditional treatments can only alleviate secondary injuries but cannot fundamentally repair the spinal cord. Consequently, there is a critical need to develop new treatments to promote functional repair after spinal cord injury. Over recent years, there have been several developments in the use of stem cell therapy for the treatment of spinal cord injury. Alongside significant developments in the field of tissue engineering, three-dimensional bioprinting technology has become a hot research topic due to its ability to accurately print complex structures. This led to the loading of three-dimensional bioprinting scaffolds which provided precise cell localization. These three-dimensional bioprinting scaffolds could repair damaged neural circuits and had the potential to repair the damaged spinal cord. In this review, we discuss the mechanisms underlying simple stem cell therapy, the application of different types of stem cells for the treatment of spinal cord injury, and the different manufacturing methods for three-dimensional bioprinting scaffolds. In particular, we focus on the development of three-dimensional bioprinting scaffolds for the treatment of spinal cord injury.

Spinal cord injury (SCI) is a prevalent and significant injury to the central nervous system, resulting in severe consequences. This injury is characterized by motor, sensory, and excretory dysfunctions below the affected spinal segment. Transplantation of bone marrow mesenchymal stem cells (BMSCs) has emerged as a potential treatment for SCI. However, the low survival as well as the differentiation rates of BMSCs within the spinal cord microenvironment significantly limit their therapeutic efficiency. Tauroursodeoxycholic acid (TUDCA), an active ingredient found in bear bile, has demonstrated its neuroprotective, antioxidant, and antiapoptotic effects on SCI. Thus, the present study was aimed to study the possible benefits of combining TUDCA with BMSC transplantation using an animal model of SCI. The results showed that TUDCA significantly enhanced BMSC viability and reduced apoptosis (assessed by Annexin V-FITC, TUNEL, Bax, Bcl-2, and Caspase-3) as well as oxidative stress (assessed by ROS, GSH, SOD, and MDA) both in vitro and in vivo. Additionally, TUDCA accelerated tissue regeneration (assessed by HE, Nissl, MAP2, MBP, TUJ1, and GFAP) and improved functional recovery (assessed by BBB score) following BMSC transplantation in SCI. These effects were mediated via the Nrf-2 signaling pathway, as evidenced by the upregulation of Nrf-2, NQO-1, and HO-1 expression levels. Overall, these results indicate that TUDCA could serve as a valuable adjunct to BMSC transplantation therapy for SCI, potentially enhancing its therapeutic efficacy.

Bone metastasis (BM) is a frequent complication associated with advanced cancer that significantly increases patient mortality. Myeloid-derived suppressor cells (MDSCs) play a pivotal role in BM progression by promoting angiogenesis, inhibiting immune responses, and inducing osteoclastogenesis. MDSCs induce immunosuppression through diverse mechanisms, including the generation of reactive oxygen species, nitric oxide, and immunosuppressive cytokines. Within the bone metastasis niche (BMN), MDSCs engage in intricate interactions with tumor, stromal, and bone cells, thereby establishing a complex regulatory network. The biological activities and functions of MDSCs are regulated by the microenvironment within BMN. Conversely, MDSCs actively contribute to microenvironmental regulation, thereby promoting BM development. A comprehensive understanding of the indispensable role played by MDSCs in BM is imperative for the development of novel therapeutic strategies. This review highlights the involvement of MDSCs in BM development, their regulatory mechanisms, and their potential as viable therapeutic targets.

We aimed to evaluate the role of the spinal lymphatic system in spinal cord injury and whether it has an impact on recovery after spinal cord injury. Flow cytometry was used to evaluate the changes in the number of microvesicles after spinal cord injury. Evans blue extravasation was used to evaluate the function of the lymphatic system. Evans blue extravasation and immunofluorescence were used to evaluate the permeability of blood spinal cord barrier. The spinal cord edema was evaluated by dry and wet weight.Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay was used to evaluate apoptosis after spinal cord injury. Nuclear factor-kappa B pathway was detected by Western blot. Behavioral tests were used to evaluate limb function. Microvesicles released after spinal cord injury can enter the thoracic duct and then enter the blood through the lymph around the spine. After ligation of the thoracic duct, it can aggravate the neuropathological manifestations and limb function after spinal cord injury. The potential mechanism may involve nuclear factor-kappa B pathway.

Spinal cord injury (SCI) represents a severe trauma to the nervous system, leading to significant neurological damage, chronic inflammation, and persistent neuropathic pain. Current treatments, including pharmacotherapy, immobilization, physical therapy, and surgical interventions, often fall short in fully addressing the underlying pathophysiology and resultant disabilities. Emerging research in the field of regenerative medicine has introduced innovative approaches such as autologous orthobiologic therapies, with bone marrow aspirate (BMA) being particularly notable for its regenerative and anti-inflammatory properties. This review focuses on the potential of BMA to modulate inflammatory pathways, enhance tissue regeneration, and restore neurological function disrupted by SCI. We hypothesize that BMA's bioactive components may stimulate reparative processes at the cellular level, particularly when applied at strategic sites like the sacral hiatus to influence lumbar centers and higher neurological structures. By exploring the mechanisms through which BMA influences spinal repair, this review aims to establish a foundation for its application in clinical settings, potentially offering a transformative approach to SCI management that extends beyond symptomatic relief to promoting functional recovery.

Previous assessments of stem cell therapy for spinal cord injuries (SCI) have encountered challenges and constraints. Current research primarily emphasizes safety in early-phase clinical trials, while systematic reviews prioritize effectiveness, often overlooking safety and translational feasibility. This situation prompts inquiries regarding the readiness for clinical adoption.

To offer an up-to-date systematic literature review of clinical trial results con cerning stem cell therapy for SCI.

A systematic search was conducted across major medical databases [PubMed, Embase, Reference Citation Analysis (RCA), and Cochrane Library] up to October 14, 2023. The search strategy utilized relevant Medical Subject Heading (MeSH) terms and keywords related to "spinal cord", "injury", "clinical trials", "stem cells", "functional outcomes", and "adverse events". Studies included in this review consisted of randomized controlled trials and non-randomized controlled trials reporting on the use of stem cell therapies for the treatment of SCI.

In a comprehensive review of 66 studies on stem cell therapies for SCI, 496 papers were initially identified, with 237 chosen for full-text analysis. Among them, 236 were deemed eligible after excluding 170 for various reasons. These studies encompassed 1086 patients with varying SCI levels, with cervical injuries being the most common (42.2%). Bone marrow stem cells were the predominant stem cell type used (71.1%), with various administration methods. Follow-up durations averaged around 84.4 months. The 32.7% of patients showed functional impro vement from American spinal injury association Impairment Scale (AIS) A to B, 40.8% from AIS A to C, 5.3% from AIS A to D, and 2.1% from AIS B to C. Sensory improvements were observed in 30.9% of patients. A relatively small number of adverse events were recorded, including fever (15.1%), headaches (4.3%), muscle tension (3.1%), and dizziness (2.6%), highlighting the potential for SCI recovery with stem cell therapy.

In the realm of SCI treatment, stem cell-based therapies show promise, but clinical trials reveal potential adverse events and limitations, underscoring the need for meticulous optimization of transplantation conditions and parameters, caution against swift clinical implementation, a deeper understanding of SCI pathophysiology, and addressing ethical, tumorigenicity, immunogenicity, and immunotoxicity concerns before gradual and careful adoption in clinical practice.

Anodal transcranial direct current stimulation (AtDCS), a neuromodulatory technique, has been applied to treat traumatic brain injury (TBI) in patients and was reported to promote functional improvement. We evaluated the effect of contralesional AtDCS on axonal sprouting of the intact corticospinal tract (CST) and the underlying mechanism in a TBI mouse model to provide more preclinical evidence for the use of AtDCS to treat TBI.

TBI was induced in mice by a contusion device. Then, the mice were subjected to contralesional AtDCS 5 days per week followed by a 2-day interval for 7 weeks. After AtDCS, motor function was evaluated by the irregular ladder walking, narrow beam walking, and open field tests. CST sprouting was assessed by anterograde and retrograde labeling of corticospinal neurons (CSNs), and the effect of AtDCS was further validated by pharmacogenetic inhibition of axonal sprouting using clozapine-N-oxide (CNO).

TBI resulted in damage to the ipsilesional cortex, while the contralesional CST remained intact. AtDCS improved the skilled motor functions of the impaired hindlimb in TBI mice by promoting CST axon sprouting, specifically from the intact hemicord to the denervated hemicord. Furthermore, electrical stimulation of CSNs significantly increased the excitability of neurons and thus activated the mechanistic target of rapamycin (mTOR) pathway.

Contralesional AtDCS improved skilled motor following TBI, partly by promoting axonal sprouting through increased neuronal activity and thus activation of the mTOR pathway.

To investigate the effect and mechanism of Tetramethylpyrazine (TMP) in treating Spinal Cord Injury (SCI) using network pharmacology analysis and animal experiments.

This study was based on public databases, including PharmMapper, BATMAN-TCM, and STRING, as well as KEGG pathway analysis and other methods of network pharmacology were used to preliminarily explore the molecular mechanism of TMP in the treatment of SCI. Using a mouse SCI compression injury model, the efficacy of TMP was evaluated, and the expression of predictive targets on the PI3K/AKT and MAPK signaling pathways was measured using Western blotting and q-PCR.

Network pharmacology analysis showed that TMP may exert therapeutic effects through the MAPK and PI3K/AKT signaling pathways. In animal experimental validation studies, it was shown that after treatment with TMP, the hind limb motor function scores and ramp test scores of the TMP-treated mice improved significantly. HE staining showed that after treatment with TMP, cavities decreased, fewer glial cells proliferated, and fewer inflammatory cells infiltrated; Nielsen staining showed less neuronal loss. Western blot studies showed that compared with the model group, expression of RAS, ERK1/2, RAF1, PI3K, and p-AKT proteins in the spinal cord tissue of mice treated with high-dose TMP was significantly lower. Accordingly, q-PCR studies showed that compared with the model group, the expression levels of RAS, ERK1/2, RAF1, PI3K, and p-AKT genes in the spinal cords of mice in the high-dose TMP group were significantly lower.

TMP exhibits a good neuroprotective effect after SCI, which may be related to inhibition of the MAPK and PI3K/AKT signaling pathways.

To investigate the effect of M2 microglia (M2-MG) transplantation on spinal cord injury (SCI) repair in mice.

Primary MG were obtained from the cerebral cortex of 15 C57BL/6 mice born 2-3 days old by pancreatic enzyme digestion and identified by immunofluorescence staining of Iba1. Then the primary MG were co-cultured with interleukin 4 for 48 hours (experimental group) to induce into M2 phenotype and identified by immunofluorescence staining of Arginase 1 (Arg-1) and Iba1. The normal MG were harvested as control (control group). The dorsal root ganglion (DRG) of 5 C57BL/6 mice born 1 week old were co-cultured with M2-MG for 5 days to observe the axon length, the DRG alone was used as control. Forty-two 6-week-old female C57BL/6 mice were randomly divided into sham group ( n=6), SCI group ( n=18), and SCI+M2-MG group ( n=18). In sham group, only the laminae of T 10 level were removed; SCI group and SCI+M2-MG group underwent SCI modeling, and SCI+M2-MG group was simultaneously injected with M2-MG. The survival of mice in each group was observed after operation. At immediate (0), 3, 7, 14, 21, and 28 days after operation, the motor function of mice was evaluated by Basso Mouse Scale (BMS) score, and the gait was evaluated by footprint experiment at 28 days. The spinal cord tissue was taken after operation for immunofluorescence staining, in which glial fibrillary acidic protein (GFAP) staining at 7, 14, and 28 days was used to observe the injured area of the spinal cord, neuronal nuclei antigen staining at 28 days was used to observe the survival of neurons, and GFAP/C3 double staining at 7 and 14 days was used to observe the changes in the number of A1 astrocytes.

The purity of MG in vitro reached 90%, and the most of the cells were polarized into M2 phenotype identified by Arg-1 immunofluorescence staining. M2-MG promoted the axon growth when co-cultured with DRGs in vitro ( P<0.05). All groups of mice survived until the experiment was completed. The hind limb motor function of SCI group and SCI+M2-MG group gradually recovered over time. Among them, the SCI+M2-MG group had significantly higher BMS scores than the SCI group at 21 and 28 days ( P<0.05), and the dragging gait significantly improved at 28 days, but it did not reach the level of the sham group. Immunofluorescence staining showed that compared with the SCI group, the SCI+M2-MG group had a smaller injury area at 7, 14, and 28 days, an increase in neuronal survival at 28 days, and a decrease in the number of A1 astrocytes at 7 and 14 days, with significant differences ( P<0.05).

M2-MG transplantation improves the motor function of the hind limbs of SCI mice by promoting neuron survival and axon regeneration. This neuroprotective effect is related to the inhibition of A1 astrocytes polarization.

Adolescent binge drinking leads to long-lasting disorders of the adult central nervous system, particularly aberrant hippocampal neurogenesis. In this study, we applied in vivo fluorescent tracing using NestinCreERT2::Rosa26-tdTomato mice and analyzed the endogenous neurogenesis lineage progression of neural stem cells (NSCs) and dendritic spine formation of newborn neurons in the subgranular zone of the dentate gyrus. We found abnormal orientation of tamoxifen-induced tdTomato+ (tdTom+) NSCs in adult mice 2 months after treatment with EtOH (5.0 g/kg, i.p.) for 7 consecutive days. EtOH markedly inhibited tdTom+ NSCs activation and hippocampal neurogenesis in mouse dentate gyrus from adolescence to adulthood. EtOH (100 mM) also significantly inhibited the proliferation to 39.2% and differentiation of primary NSCs in vitro. Adult mice exposed to EtOH also exhibited marked inhibitions in dendritic spine growth and newborn neuron maturation in the dentate gyrus, which was partially reversed by voluntary running or inhibition of the mammalian target of rapamycin-enhancer of zeste homolog 2 pathway. In vivo tracing revealed that EtOH induced abnormal orientation of tdTom+ NSCs and spatial misposition defects of newborn neurons, thus causing the disturbance of hippocampal neurogenesis and dendritic spine remodeling in mice.

Spinal cord injury (SCI) can lead to severe motor, sensory and autonomic nervous dysfunction, cause serious psychosomatic injury to patients. There is no effective treatment for SCI at present. In recent years, exciting evidence has been obtained in the application of cell-based therapy in basic research. These studies have revealed the fact that cells transplanted into the host can exert the pharmacological properties of treating and repairing SCI. Olfactory ensheathing cells (OECs) are a kind of special glial cells. The application value of OECs in the study of SCI lies in their unique biological characteristics, that is, they can survive and renew for life, give full play to neuroprotection, immune regulation, promoting axonal regeneration and myelination formation. The function of producing secretory group and improving microenvironment. This provides an irreplaceable treatment strategy for the repair of SCI. At present, some researchers have explored the possibility of treatment of OECs in clinical trials of SCI. Although OECs transplantation shows excellent safety and effectiveness in animal models, there is still lack of sufficient evidence to prove the effectiveness of their clinical application in clinical trials. There has been an obvious stagnation in the transformation of OECs transplantation into routine clinical practice, and clinical trials of cell therapy in this field are still facing major challenges and many problems that need to be solved. Therefore, this paper summarized and analyzed the clinical trials of OECs transplantation in the treatment of SCI, and discussed the problems and challenges of OECs transplantation in clinical trials.

Balance is the dynamic and unconscious control of the body's centre of mass to maintain postural equilibrium. Regulated by the vestibular system, head movement and acceleration are processed by the brain to adjust joints. Several conditions result in a loss of balance, including Alzheimer's Disease, Parkinson's Disease, Menière's Disease and cervical spondylosis, all of which are caused by damage to certain parts of the vestibular pathways. Studies about the impairment of the vestibular system are challenging to carry out in human trials due to smaller study sizes limiting applications of the results and a lacking understanding of the human balance control mechanism. In contrast, more controlled research can be performed in animal studies which have fewer confounding factors than human models and allow specific conditions that affect balance to be replicated. Balance control can be studied using rodent balance-related behavioural tests after spinal or brain lesions, such as the Basso, Beattie and Bresnahan (BBB) Locomotor Scale, Foot Fault Scoring System, Ledged Beam Test, Beam Walking Test, and Ladder Beam Test, which are discussed in this review article along with their advantages and disadvantages. These tests can be performed in preclinical rodent models of femoral nerve injury, stroke, spinal cord injury and neurodegenerative diseases.

Ferroptosis has been proven critical for survival following bone marrow mesenchymal stem cells (BMSCs) explantation. Suppression of ferroptosis in BMSCs will be a valid tactic to elevate the therapeutic potential of engrafted BMSCs. Prominin2 is a pentaspanin protein involved in mediating iron efflux and thus modulates resistance to ferroptosis, but its role in tert-butyl hydroperoxide (TBHP)-induced BMSCs ferroptosis remains elusive. We examined the biological effect of prominin2 in vitro and in vivo by using cell proliferation assay, iron assay, reactive oxygen species (ROS) examination, malondialdehyde assay, glutathione (GSH) examination, Western blot, quantitative reverse transcription-PCR, immunofluorescence staining assay, gene expression inhibition and activation, co-immunoprecipitation (CO-IP) assay, radiographic analysis, and histopathological analysis. Our study demonstrated that prominin2 activity was impaired in TBHP-induced BMSCs ferroptosis. We found that PROM2 (encoding the protein prominin2) activation delayed the onset of ferroptosis and PROM2 knockdown deteriorated the course of ferroptosis. CO-IP, Western blot, and immunofluorescence demonstrated that prominin2 exerts antiferroptosis effects by inhibiting BTB and CNC homology 1 (BACH1) that promotes ROS generation, and thus exerts potent antioxidant effects in oxidative stress (OS)-induced BMSCs ferroptosis, including elevating BMSCs' survival rate and enhancing GSH contents. BMSCs with PROM2 overexpression also partially delayed the progression of intervertebral disk degeneration in vivo, as illustrated by less loss of disk height and lower histological scores. Our findings revealed a mechanism that the prominin2/BACH1/ROS axis participates in BMSCs ferroptosis and the strengthening of this axis is promising to maintain BMSCs' survival after explantation.NEW & NOTEWORTHY We found that prominin2 might be a potential biomarker and is expected to be utilized to augment engrafted bone marrow mesenchymal stem cells (BMSCs) survival rate. The prominin2/BTB and CNC homology 1 (BACH1)/reactive oxygen species (ROS) axis, which participates in the regulation of BMSCs ferroptosis induced by tert-butyl hydroperoxide (TBHP), is uncovered in our study. The therapeutic targeting of the prominin2/BACH1/ROS axis components is promising to elevate the survival of transplanted BMSCs in clinical practice.

Liver transplantation (LT) is the only effective therapy for end-stage liver diseases, but some patients usually present with serious infection and immune rejection. Those with immune rejection require long-term administration of immunosuppressants, leading to serious adverse effects. Mesenchymal stem cells (MSCs) have various advantages in immune regulation and are promising drugs most likely to replace immunosuppressants.

This study summarized the application of MSCs monotherapy, its combination with immunosuppressants, MSCs genetic modification, and MSCs derivative therapy (cell-free therapy) in LT. This may deepen the understanding of immunomodulatory role of MSCs and promote the application of MSCs in immune rejection treatment after LT.

MSCs could attenuate ischemia-reperfusion injury and immune rejection. There is no consensus on the effects of types and concentrations of immunosuppressants on MSCs. Although genetically modified MSCs have contributed to better outcomes to some extent, the best modification is still unclear. Besides, multiple clinical complications developed frequently after LT. Unfortunately, there are still few studies on the polygenic modification of MSCs for the simultaneous treatment of these complications. Therefore, more studies should be performed to investigate the potency of multi-gene modified MSCs in treating complications after LT. Additionally, MSC derivatives mainly include exosomes, extracellular vesicles, and conditioned medium. Despite therapeutic effects, these three therapies still have some limitations such as heterogeneity between generations and that they cannot be quantified accurately.

Functional hydrogels show potential application in repairing spinal cord injury (SCI) due to their unique chemical, physical, and biological properties and functions. In this comprehensive review, we present recent advance in the material design, functional regulation, and SCI repair applications of bioactive hydrogels. Different from previously released reviews on hydrogels and three-dimensional scaffolds for the SCI repair, this work focuses on the strategies for material design and biologically functional regulation of hydrogels, specifically aiming to show how these significant efforts can promoting the repairing performance of SCI. We demonstrate various methods and techniques for the fabrication of bioactive hydrogels with the biological components such as DNA, proteins, peptides, biomass polysaccharides, and biopolymers to obtain unique biological properties of hydrogels, including the cell biocompatibility, self-healing, anti-bacterial activity, injectability, bio-adhesion, bio-degradation, and other multi-functions for repairing SCI. The functional regulation of bioactive hydrogels with drugs/growth factors, polymers, nanoparticles, one-dimensional materials, and two-dimensional materials for highly effective treating SCI are introduced and discussed in detail. This work shows new viewpoints and ideas on the design and synthesis of bioactive hydrogels with the state-of-the-art knowledges of materials science and nanotechnology, and will bridge the connection of materials science and biomedicine, and further inspire clinical potential of bioactive hydrogels in biomedical fields.

Exercise has well-recognized beneficial effects on the whole body. Previous studies suggest that exercise could promote tissue regeneration and repair in various organs. In this review, we have summarized the major effects of exercise on tissue regeneration primarily mediated by stem cells and progenitor cells in skeletal muscle, nervous system, and vascular system. The protective function of exercise-induced stem cell activation under pathological conditions and aging in different organs have also been discussed in detail. Moreover, we have described the primary molecular mechanisms involved in exercise-induced tissue regeneration, including the roles of growth factors, signaling pathways, oxidative stress, metabolic factors, and non-coding RNAs. We have also summarized therapeutic approaches that target crucial signaling pathways and molecules responsible for exercise-induced tissue regeneration, such as IGF1, PI3K, and microRNAs. Collectively, the comprehensive understanding of exercise-induced tissue regeneration will facilitate the discovery of novel drug targets and therapeutic strategies.

Spinal cord injury (SCI) has considerable impact on patient physical, mental, and financial health. Secondary SCI is associated with inflammation, vascular destruction, and subsequent permanent damage to the nervous system. Mesenchymal stem cells (MSCs) have anti-inflammatory properties, promoting vascular regeneration and the release neuro-nutrients, and are a promising strategy for the treatment of SCI. Preclinical studies have shown that MSCs promote sensory and motor function recovery in rats. In clinical trials, MSCs have been reported to improve the American Spinal Injury Association (ASIA) sensory and motor scores. However, the effectiveness of MSCs in treating patients with SCI remains controversial. MSCs promote tumorigenesis and ensuring the survival of MSCs in the hostile environment of SCI is challenging. In this article we examine the evidence on the pathophysiological changes occurring after SCI. We then review the underlying mechanisms of MSCs in the treatment of SCI and summarize the potential application of MSCs in clinical practice. Finally, we highlight the challenges surrounding the use of MSCs in the treatment of SCI and discuss future applications.