The immune microenvironment significantly influences neural regeneration in spinal cord injury (SCI). Lactate activates central nervous system (CNS) glial cells, prompting the secretion of proinflammatory cytokines and triggering an inflammatory response. Mesenchymal stem cells (MSCs) make a promising future for SCI therapy due to their immune regulation and anti-inflammatory properties. However, it is unclear whether MSCs inhibit inflammatory responses in the SCI microenvironment through lactylation regulation. This study aimed to identify lactylation-related genes (LRGs) in SCI and investigate their role in immune cell infiltration and MSC-mediated inflammation reduction.

Transcription datasets of SCI patients were acquired from Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) underwent functional enrichment analysis, and CIBERSORT assessed immune cell infiltration in SCI. Crucial lactylation-related differentially expressed genes (LRDEGs) associated with SCI were identified via machine learning. The association between LRDEGs and inflammatory response in SCI mediated by immune cell infiltration was confirmed using Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG). Rats with subacute thoracic SCI were transplanted with hUC-MSCs, and transcriptome analyses were conducted on their spinal cords and retrieved hUC-MSCs, respectively.

The study identified 808 DEGs and 13 differentially infiltrated immune cell types in SCI patients compared to healthy controls. Multiple inflammatory response-related signaling pathways were activated in SCI. Seven LRDEGs, including LSP1, XRCC4, HSDL2, HNRNPH1, RPL14, IKZF1, and TP53, were recognized as key regulators. These genes are linked to immune cell infiltration and inflammatory responses in SCI. In SCI rats, the increased expression of LRDEGs and inflammatory cytokines were observed, which were significantly reduced after hUC-MSC transplantation. Differences in LRDEG expression patterns, enriched functions, and pathways between two SCI subtypes were statistically significant.

LRDEGs are involved in immune cell-mediated inflammatory response in SCI, and hUC-MSC transplantation reduces LRDEGs expression and inflammation response in the SCI microenvironment.

Nerve damage can cause abnormal motor and sensory consequences, including lifelong paralysis if not surgically restored. The yearly cost of healthcare in the United States is projected to be $150 billion, and millions of Americans suffer from peripheral nerve injuries as a result of severe traumas and disorders. For nerve injuries, the outcome of conventional therapies is suboptimal and may have unfavorable side effects. However, mesenchymal stem cells (MSCs) have been proven to be a viable option for the reconstruction of injured nerve tissue and bring a ray of hope. These stem cells are derived from bone marrow, adipose tissue, and human umbilical cord blood and have the ability to secrete trophic factors, contribute to the immune system, and stimulate axonal regeneration. The purpose of this review is to examine the potential benefits of MSCs for enhancing functional recovery and patient prognosis by highlighting their characteristics and elucidating their mechanism of action in nerve injury healing.

Spinal cord injuries (SCIs) impact between 250,000 and 500,000 people worldwide annually, often resulting from road accidents or falls. These injuries frequently lead to lasting disabilities, with the severity depending on the injury's extent and location. Emerging research also links SCIs to cognitive impairments due to brain inflammation. From a treatment perspective, various approaches, including cell therapy, have been investigated. One common mechanism across cellular transplant models is the modulation of inflammation at the injury site, though it remains uncertain if these effects extend to the brain. To explore this, we induced SCI in wild-type mice and treated them with either olfactory ensheathing cells or mesenchymal stem cells. Our findings reveal that both cell types can reverse SCI-induced cognitive deficits, reduce brain inflammation, and increase hippocampal neuronal density. This study is the first, to our knowledge, to demonstrate that cells transplanted into the spinal cord can influence brain inflammation and mitigate injury-induced effects on brain functions. These results highlight the intricate relationship between the spinal cord and brain in both health and disease.

This article discusses the peculiarities of microglia behaviour and their interaction with other cells of the central nervous system (CNS) during neural tissue injury with a focus on spinal cord injury (SCI). Taking into account the plasticity of microglia, the influence of the microenvironment should be taken into account to establish the mechanisms determining the polarization pathways of these cells. Determination of the system of microglia interactions with other CNS cells during injury will reveal the patterns of post-traumatic microglia responses, in particular, determining both pro-inflammatory and anti-inflammatory responses. This review compiles information on changes in microglia activation, migration and phagocytosis, as well as their reciprocal effects on other CNS cells, such as neurons, astrocytes and oligodendrocytes, in the background of SCI. The information contained in this article may be of interest not only to scientists studying traumatic injuries of the central nervous system, but also to specialists in the field of studying and treating neurodegenerative diseases, since the mechanisms occurring in the injured spinal cord may also be characteristic of pathological events in degenerative processes.

Spinal cord injury (SCI) can lead to severe motor and sensory dysfunction, with a high rate of disability and mortality. Due to the complicated pathological process of SCI, there is no effective clinical treatment strategy at present. Although mesenchymal stem cells (MSCs) are effective in the treatment of SCI, their application is limited by factors such as low survival rate, cell dedifferentiation, tumorigenesis, blood-brain barrier, and immune rejection. Fortunately, there is growing evidence that most of the biological and therapeutic effects of MSCs may be mediated by the release of paracrine factors, which are extracellular vesicles called exosomes. Exosomes are small endosomal vesicles with bilaminar membranes that have recently been recognized as key mediators for communication between cells and tissues through the transfer of proteins, lipids, nucleic acids, cytokines, and growth factors. Mesenchymal stem cell-derived exosomes (MSC-exos) play a critical role in SCI repair by promoting angiogenesis and axonal growth, regulating inflammation and immune response, inhibiting apoptosis, and maintaining the integrity of the blood-spinal cord barrier. Furthermore, they can be used to transport genetic material or drugs to target cells, and their relatively small size allows them to permeate the blood-brain barrier. Studies have demonstrated that some exosomal miRNAs derived from MSCs play a significant role in the treatment of SCI. In this review, we summarize recent research advances in MSC-exos and exosomal miRNAs in SCI therapy to better understand this emerging cell-free therapeutic strategy and discuss the advantages and challenges of MSC-exos in future clinical applications.

Spinal cord injury (SCI) is a common nerve injury caused by external force, resulting in sensory and motor impairments. Previous studies demonstrated that inhibiting the neuroinflammation promoted SCI repair. However, these approaches are low efficient, and lack targeting specificity, and even require repeated and high doses of systemic administration. To address such issues, in the present study, chitosan-modified hydrogel microspheres encapsulating with zinc-doped bioactive glasses (CS-MG@Zn/BGs) is constructed for targeted repair of SCI. In vitro, the CS-MG@Zn/BGs effectively inhibited the acute inflammatory response initiated by microglia and promoted angiogenic activities. In vivo, CS-MG@Zn/BGs targeted the injured site, and attenuated neuroinflammation by inhibiting microglia infiltration and modulating microglia polarization toward M2 type. Furthermore, it facilitated vascular reconstruction, neuronal differentiation, axonal regeneration and remyelination at the injured site, and thereby promoted motor function recovery of SCI mice. The in vitro and in vivo results implied that CS-MG@Zn/BGs may be a promising alternative for the rehabilitation of SCI.

Idiopathic Pulmonary Fibrosis (IPF) is a type of interstitial lung disease characterized by chronic inflammation due to persistent lung damage. Mesenchymal stem cells (MSCs), including those derived from the umbilical cord (UCMSCs) and placenta (PLMSCs), have been utilized in clinical trials for IPF treatment. However, the varying therapeutic effectiveness between these two MSC types remains unclear.

In this study, we examined the therapeutic differences between UCMSCs and PLMSCs in treating lung damage using a bleomycin (BLM)-induced pulmonary injury mouse model.

We showed that UCMSCs had a superior therapeutic impact on lung damage compared to PLMSCs. Upon cytokine stimulation, UCMSCs expressed higher levels of inflammation-related genes and more effectively directed macrophage polarization towards the M2 phenotype than PLMSCs, both in vitro and in vivo. Furthermore, UCMSCs showed a preference for expressing CC motif ligation 2 (CCL2) and C-X-C motif chemokine ligand 1 (CXCL1) compared to PLMSCs. The expression of secreted phosphoprotein 1 (SPP1), triggering receptor expressed on myeloid cells 2 (Trem2), and CCAAT enhancer binding protein beta (Cebpb) in macrophages from mice with the disease treated with UCMSCs was significantly reduced compared to those treated with PLMSCs.

Therefore, UCMSCs demonstrated superior anti-fibrotic abilities in treating lung damage, potentially through inducing a more robust M2 polarization of macrophages than PLMSCs.

Spinal cord injury (SCI) disrupts the blood-spinal cord barrier (BSCB) exacerbating damage by allowing harmful substances and immune cells to infiltrate spinal neural tissues from the vasculature. This leads to inflammation, oxidative stress, and impaired axonal regeneration. The BSCB, essential for maintaining spinal cord homeostasis, is structurally similar to the blood-brain barrier. Its restoration is a key therapeutic target for improving outcomes in SCI. Mesenchymal stromal/stem cells (MSCs) and their secreted extracellular vesicles (MSC-EVs) have gained attention for their regenerative, immunomodulatory, and anti-inflammatory properties in promoting BSCB repair. MSCs enhance BSCB integrity by improving endothelial-pericyte association, restoring tight junction proteins, and reducing inflammation. MSC-EVs, which deliver bioactive molecules, replicate many of MSCs' therapeutic effects, and offer a promising cell-free alternative. Preclinical studies have shown that both MSCs and MSC-EVs can reduce BSCB permeability, promote vascular stability, and support functional recovery. While MSC therapy is advancing in clinical trials, MSC-EV therapies require further optimization in terms of production, dosing, and delivery protocols. Despite these challenges, both therapeutic approaches represent significant potential for treating SCI by targeting BSCB repair and improving patient outcomes.

Spinal cord injury (SCI) affects around 18,000 individuals annually, representing nearly one-third of all paralysis cases. Stem cell therapy, a focal point in contemporary neuroregeneration research for SCI treatment, holds potential in leveraging undifferentiated stem cells to regenerate damaged tissues. This study seeks to comprehensively analyze current clinical trials exploring the potential use of stem cells in treating spinal cord injuries.

A data retrieval approach examined the ClinicalTrials.gov database using the terms "spinal cord injury" and "stem cells." Exclusion criteria eliminated studies not recruiting, terminated prematurely, suspended, withdrawn, or of unknown status. Data for each trial, including ClinicalTrial.gov NCT identifier, title, intervention details, initiation/completion dates, and sample size, were systematically collected. Literature searches on PubMed.gov were conducted for completed trials with results.

Thirty clinical trials were analyzed, with 20 completed and six with published results on PubMed.gov. Interventions included 20 biological (66.7%), 6 procedural (20%), and 4 drug interventions (13.3%). Stem cell sources varied, including bone marrow (46.7%), umbilical cells (20%), adipose tissue (20%), embryonic cells (6.7%), and neural cells (6.7%). Trials spanned 2005 to 2022, with 11 (36.7%) commencing in or after 2017. Among six trials with results, 50% used bone marrow-derived stem cells.

The promising potential of stem cells in neuroregenerative SCI treatment necessitates further exploration through large-scale, multicenter clinical trials to enhance understanding and guide wider adoption of this emerging treatment paradigm.

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.

Inflammatory arthritis are common chronic inflammatory autoimmune diseases characterised by progressive, destructive inflammation of the joints leading to a loss of function and significant comorbidities; importantly, there are no cures and only 20% of patients achieve drug-free remission for over 2 years. Macrophages play a vital role in maintaining homeostasis, however, under the wrong environmental cues, become drivers of chronic synovial inflammation. Based on the current "dogma", M1 macrophages secrete pro-inflammatory cytokines and chemokines, promoting tissue degradation and joint and bone erosion which over time lead to accelerated disease progression. On the other hand, M2 macrophages secrete anti-inflammatory mediators associated with wound healing, tissue remodelling and the resolution of inflammation. Currently, four subtypes of M2 macrophages have been identified, namely M2a, M2b, M2c and M2d. However, more subtypes may exist due to macrophage plasticity and the ability for repolarisation. Macrophages are highly plastic, and polarisation exists as a continuum with diverse intermediate phenotypes. This plasticity is achieved by a highly amenable epigenome in response to environmental stimuli and shifts in metabolism. Initiating treatment during the early stages of disease is important for improved prognosis and patient outcomes. Currently, no treatment targeting macrophages specifically is available. Such therapeutics are being investigated in ongoing clinical trials. The repolarisation of pro-inflammatory macrophages towards the anti-inflammatory phenotype has been proposed as an effective approach in targeting the M1/M2 imbalance, and in turn is a potential therapeutic strategy for IA diseases. Therefore, elucidating the mechanisms that govern macrophage plasticity is fundamental for the success of novel macrophage targeting therapeutics.

Spinal cord injury (SCI) is a serious medical condition. The search for an effective cure remains a persistent challenge. Current treatments, unfortunately, are unable to sufficiently improve neurological function, often leading to lifelong disability. This systematic review and meta-analysis evaluated the effectiveness of stem cell therapy for SCI using canine models. It also explored the optimal protocol for implementing stem cell therapy. A comprehensive search of studies was conducted from 2000 to October 2022. This study focused on five outcomes: motor function score, histopathology, IHC, western blot, and SEP. The results demonstrated a significant improvement in locomotion post-SCI in dogs treated with stem cell therapy. The therapy also led to an average increase of 3.15 points in the Olby score of the treated dogs compared to the control group. These findings highlights stem cell therapy's potential as a promising SCI treatment. The meta-analysis suggests that using bone marrow stem cells, undergoing neural differentiation in vitro, applying a surgical implantation or intrathecal route of administration, associating matrigel in combination with stem cells, and a waiting period of two weeks before starting treatment can enhance SCI treatment effectiveness.

Spinal cord injury (SCI) is a debilitating condition that is associated with long-term physical and functional disability. Our understanding of the pathogenesis of SCI has evolved significantly over the past three decades. In parallel, significant advances have been made in optimizing the management of patients with SCI. Early surgical decompression, adequate bony decompression and expansile duraplasty are surgical strategies that may improve neurological and functional outcomes in patients with SCI. Furthermore, advances in the non-surgical management of SCI have been made, including optimization of hemodynamic management in the critical care setting. Several promising therapies have also been investigated in pre-clinical studies, with some being translated into clinical trials. Given the recent interest in advancing precision medicine, several investigations have been performed to delineate the role of imaging, cerebral spinal fluid (CSF) and serum biomarkers in predicting outcomes and curating individualized treatment plans for SCI patients. Finally, technological advancements in biomechanics and bioengineering have also found a role in SCI management in the form of neuromodulation and brain-computer interfaces.

Spinal cord injury (SCI) has limited treatment options for regaining function. Adipose-derived stem cells (ADSCs) show promise owing to their ability to differentiate into multiple cell types, promote nerve cell survival, and modulate inflammation. This review explores ADSC therapy for SCI, focusing on its potential for improving function, preclinical and early clinical trial progress, challenges, and future directions. Preclinical studies have demonstrated ADSC transplantation's effectiveness in promoting functional recovery, reducing cavity formation, and enhancing nerve regrowth and myelin repair. To improve ADSC efficacy, strategies including genetic modification and combination with rehabilitation are being explored. Early clinical trials have shown safety and feasibility, with some suggesting motor and sensory function improvements. Challenges remain for clinical translation, including optimizing cell survival and delivery, determining dosing, addressing tumor formation risks, and establishing standardized protocols. Future research should focus on overcoming these challenges and exploring the potential for combining ADSC therapy with other treatments, including rehabilitation and medication.

Spinal cord injury (SCI) can result in the permanent loss of mobility, sensation, and autonomic function. Secondary degeneration after SCI both initiates and propagates a hostile microenvironment that is resistant to natural repair mechanisms. Consequently, exogenous stem cells have been investigated as a potential therapy for repairing and recovering damaged cells after SCI and other CNS disorders. This focused review highlights the contributions of mesenchymal (MSCs) and dental stem cells (DSCs) in attenuating various secondary injury sequelae through paracrine and cell-to-cell communication mechanisms following SCI and other types of neurotrauma. These mechanistic events include vascular dysfunction, oxidative stress, excitotoxicity, apoptosis and cell loss, neuroinflammation, and structural deficits. The review of studies that directly compare MSC and DSC capabilities also reveals the superior capabilities of DSC in reducing the effects of secondary injury and promoting a favorable microenvironment conducive to repair and regeneration. This review concludes with a discussion of the current limitations and proposes improvements in the future assessment of stem cell therapy through the reporting of the effects of DSC viability and DSC efficacy in attenuating secondary damage after SCI.

Spinal cord injury (SCI) is a devastating condition with a complex pathology that affects a significant portion of the population and causes long-term consequences. After primary injury, an inflammatory cascade of secondary injury occurs, followed by neuronal cell death and glial scar formation. Together with the limited regenerative capacity of the central nervous system, these are the main reasons for the poor prognosis after SCI. Despite recent advances, there is still no effective treatment. Promising therapeutic approaches include stem cells transplantation, which has demonstrated neuroprotective and immunomodulatory effects in SCI. This positive effect is thought to be mediated by small extracellular vesicles (sEVs); membrane-bound nanovesicles involved in intercellular communication through transport of functional proteins and RNA molecules. In this review, we summarize the current knowledge about sEVs and microRNA as their cargo as one of the most promising therapeutic approaches for the treatment of SCI. We provide a comprehensive overview of their role in SCI pathophysiology, neuroprotective potential and therapeutic effect.

Spinal cord injury (SCI) is an intractable neurological disease in which functions cannot be permanently restored due to nerve damage. Stem cell therapy is a promising strategy for neuroregeneration after SCI. However, experimental evidence of its therapeutic effect in SCI is lacking. This study aimed to investigate the efficacy of transplanted cells using stepwise combined cell therapy with human mesenchymal stem cells (hMSC) and induced pluripotent stem cell (iPSC)-derived motor neuron progenitor cells (iMNP) in a rat model of SCI.

A contusive SCI model was developed in Sprague-Dawley rats using multicenter animal spinal cord injury study (MASCIS) impactor. Three protocols were designed and conducted as follows: (Subtopic 1) chronic SCI + iMNP, (Subtopic 2) acute SCI + multiple hMSC injections, and (Main topic) chronic SCI + stepwise combined cell therapy using multiple preemptive hMSC and iMNP. Neurite outgrowth was induced by coculturing hMSC and iPSC-derived motor neuron (iMN) on both two-dimensional (2D) and three-dimensional (3D) spheroid platforms during mature iMN differentiation in vitro.

Stepwise combined cell therapy promoted mature motor neuron differentiation and axonal regeneration at the lesional site. In addition, stepwise combined cell therapy improved behavioral recovery and was more effective than single cell therapy alone. In vitro results showed that hMSC and iMN act synergistically and play a critical role in the induction of neurite outgrowth during iMN differentiation and maturation.

Our findings show that stepwise combined cell therapy can induce alterations in the microenvironment for effective cell therapy in SCI. The in vitro results suggest that co-culturing hMSC and iMN can synergistically promote induction of MN neurite outgrowth.

The M1 polarization of microglia, followed by the production of pro-inflammatory mediators, hinders functional recovery after spinal cord injury (SCI). Our previous study has illuminated that specificity protein 1 (Sp1) expression is increased following SCI, whereas the function and regulatory mechanism of Sp1 during M1 polarization of microglia following SCI remain unknown. RNA binding protein, HuR, has been shown to be up-regulated in the injured spinal cord through analysis of the GEO database. Further investigation using Chip-Atlas data suggests a binding between Sp1 and HuR. Emerging evidence indicates that HuR plays a pivotal role in neuroinflammation after SCI. In this research, Sp1 and HuR levels in mice with SCI and BV2 cells treated with lipopolysaccharide (LPS) was determined by using quantitative real-time polymerase chain reaction and Western blotting techniques. A series of in vitro assays were performed to investigate the function of Sp1 during M1 polarization of microglia. The association between Sp1 and its target gene HuR was confirmed through gene transfection and luciferase reporter assay. Enhanced expression of HuR was observed in both SCI mice and LPS-treated BV2 cells, while Sp1 knockdown restrained M1 polarization of microglia and its associated inflammation by inhibiting the NF-κB signaling pathway. Silencing Sp1 also suppressed microglia activation and its mediated inflammatory response, which could be reversed by overexpression of HuR. In conclusion, silencing Sp1 restrains M1 polarization of microglia through the HuR/NF-κB axis, leading to neuroprotection, and thus promotes functional restoration following SCI.

White matter diseases are commonly associated with microglial activation and neuroinflammation. Mesenchymal stromal cells (MSCs) have immunomodulatory properties and thus have the potential to be developed as cell therapy for white matter disease. MSCs interact with resident macrophages to alter the trajectory of inflammation; however, the impact MSCs have on central nervous system macrophages and the effect this has on the progression of white matter disease are unclear.

In this study, we utilized numerous assays of varying complexity to model different aspects of white matter disease. These assays ranged from an in vivo spinal cord acute demyelination model to a simple microglial cell line activation assay. Our goal was to investigate the influence of human umbilical cord tissue MSCs on the activation of microglia.

MSCs reduced the production of tumor necrosis factor (TNF) by microglia and decreased demyelinated lesions in the spinal cord after acute focal injury. To determine if MSCs could directly suppress the activation of microglia and to develop an efficient potency assay, we utilized isolated primary microglia from mouse brains and the Immortalized MicroGlial Cell Line (IMG). MSCs suppressed the activation of microglia and the release of TNF after stimulation with lipopolysaccharide, a toll-like receptor agonist.

In this study, we demonstrated that MSCs altered the immune response after acute injury in the spinal cord. In numerous assays, MSCs suppressed activation of microglia and release of the pro-inflammatory cytokine TNF. Of these assays, IMG could be standardized and used as an effective potency assay to determine the efficacy of MSCs for treating white matter disease or other neuroinflammatory conditions associated with microglial activation.

Rotator cuff tear is a significant problem that leads to poor clinical outcomes due to muscle degeneration after injury. The objective of this study was to synergistically increase the number of proregenerative cells recruited to injure rotator cuff muscle through a novel dual treatment system, consisting of a bone marrow mobilizing agent (VPC01091), hypothesized to "push" prohealing cells into the blood, and localized delivery of stromal cell-derived factor-1α (SDF-1α), to "pull" the cells to the injury site. Immediately after rotator cuff tendon injury in rat, the mobilizing agent was delivered systemically, and SDF-1α-loaded heparin-based microparticles were injected into the supraspinatus muscle. Regenerative and degenerative changes to supraspinatus muscle and the presence of inflammatory/immune cells, mesenchymal stem cells (MSCs), and satellite cells were assessed via flow cytometry and histology for up to 21 days. After dual treatment, significantly more MSCs (31.9 ± 8.0% single cells) and T lymphocytes (6.7 ± 4.3 per 20 × field of view) were observed in supraspinatus muscle 7 days after injury and treatment compared to injury alone (14.4 ± 6.5% single cells, 1.2 ± 0.7 per 20 × field of view), in addition to an elevated M2:M1 macrophage ratio (3.0 ± 0.5), an indicator of a proregenerative environment. These proregenerative cellular changes were accompanied by increased nascent fiber formation (indicated by embryonic myosin heavy chain staining) at day 7 compared to SDF-1α treatment alone, suggesting that this method may be a promising strategy to influence the early cellular response in muscle and promote a proregenerative microenvironment to increase muscle healing after severe rotator cuff tear.

Spinal cord injury (SCI) is a highly disabling central nervous system injury with a complex pathological process, resulting in severe sensory and motor dysfunction. The current treatment modalities only alleviate its symptoms and cannot effectively intervene or treat its pathological process. Many studies have reported that the transforming growth factor (TGF)-β signaling pathway plays an important role in neuronal differentiation, growth, survival, and axonal regeneration after central nervous system injury. Furthermore, the TGF-β signaling pathway has a vital regulatory role in SCI pathophysiology and neural regeneration. Following SCI, regulation of the TGF-β signaling pathway can suppress inflammation, reduce apoptosis, prevent glial scar formation, and promote neural regeneration. Due to its role in SCI, the TGF-β signaling pathway could be a potential therapeutic target. This article reported the pathophysiology of SCI, the characteristics of the TGF-β signaling pathway, the role of the TGF-β signaling pathway in SCI, and the latest evidence for targeting the TGF-β signaling pathway for treating SCI. In addition, the limitations and difficulties in TGF-β signaling pathway research in SCI are discussed, and solutions are provided to address these potential challenges. We hope this will provide a reference for the TGF-β signaling pathway and SCI research, offering a theoretical basis for targeted therapy of SCI.

Traumatic spinal cord injury (SCI) results in partial or complete motor deficits, such as paraplegia, tetraplegia, and sphincter control, as well as sensory disturbances and autonomic dysregulation such as arterial hypotension, lack of sweating, and alterations in skin lability. All this has a strong psychological impact on the affected person and his/her family, as well as costs to healthcare institutions with an economic burden in the short, medium, and long terms. Despite at least forty years of experimental animal studies and several clinical trials with different therapeutic strategies, effective therapy is not universally accepted. Most of the published works on acute and chronic injury use a single treatment, such as medication, trophic factor, transplant of a cell type, and so on, to block some secondary injury mechanisms or promote some mechanisms of structural/functional restoration. However, despite significant results in experimental models, the outcome is a moderate improvement in muscle strength, sensation, or eventually in sphincter control, which has been considered non-significant in human clinical trials. Here we present a brief compilation of successful individual treatments that have been applied to secondary mechanisms of action. These studies show limited neuroprotective or neurorestorative approaches in animal models and clinical trials. Thus, the few benefits achieved so far represent a rationale to further explore other strategies that seek better structural and functional restoration of the injured spinal cord.

Herein, we investigated whether mesenchymal stem cells (MSCs) transplantation combined with electroacupuncture (EA) treatment could decrease the proportion of proinflammatory microglia/macrophages and neurotoxic A1 reactive astrocytes and inhibit glial scar formation to enhance axonal regeneration after spinal cord injury (SCI).

Adult rats were divided into 5 groups after complete transection of the spinal cord at the T10 level: a control group, a nonacupoint EA (NA-EA) group, an EA group, an MSC group, and an MSCs+EA group. Immunofluorescence labeling, quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blots were performed.

The results showed that MSCs+EA treatment reduced the proportion of proinflammatory M1 subtype microglia/macrophages, but increased the differentiation of anti-inflammatory M2 phenotype cells, thereby suppressing the mRNA and protein expression of proinflammatory cytokines (tumor necrosis factor-α and IL-1β) and increasing the expression of an anti-inflammatory cytokine (interleukin [IL]-10) on days 7 and 14 after SCI. The changes in expression correlated with the attenuated neurotoxic A1 reactive astrocytes and glial scar, which in turn facilitated the axonal regeneration of the injured spinal cord. In vitro, the proinflammatory cytokines increased the level of proliferation of astrocytes and increased the expression levels of C3, glial fibrillary acidic protein, and chondroitin sulfate proteoglycan. These effects were blocked by administering inhibitors of ErbB1 and signal transducer and activator of transcription 3 (STAT3) (AG1478 and AG490) and IL-10.

These findings showed that MSCs+EA treatment synergistically regulated the microglia/macrophage subpopulation to reduce inflammation, the formation of neurotoxic A1 astrocytes, and glial scars. This was achieved by downregulating the ErbB1-STAT3 signal pathway, thereby providing a favorable microenvironment conducive to axonal regeneration after SCI.

Abstract Spinal cord injury (SCI) is a serious neurological disorder, with the consequent disabilities conferred by this disorder typically persisting for life. Multilineage-differentiating stress-enduring (Muse) cells are endogenous stem cells that can be collected from various tissues as well as from mesenchymal stem cells (MSCs); additionally, these Muse cells are currently being used in clinical trials. The anti-inflammatory effect of stem cell transplantation prevents secondary injuries of SCI; however, its effect on Muse cells remains unclear. In this study, we aimed to compare the anti-inflammatory effects of adipose (AD)- and bone marrow (BM)-Muse cells that were isolated from mice (6-week-old C57BL/6J) following intralesional administration during the acute phase of SCI. Flow cytometry was used to isolate Muse cells from AD and BM MSCs. The percentage of Muse cells was 3.9 and 2.7% for AD and BM MSCs, respectively. To examine cell viability, Muse cells were incubated under H2O2-induced oxidative stress conditions. Overall, AD-Muse cells exhibited higher viability than BM-Muse cells (p = 0.032). In enzyme-linked immunosorbent assay analysis, AD-Muse cells displayed greater secretion of brain-derived neurotrophic factor (BDNF; p = 0.008), vascular endothelial growth factor (p = 0.032), and hepatocyte growth factor (p = 0.016). DNA microarray analysis revealed higher expression of Bdnf, neurotrophin-3 (Ntf3), nerve growth factor (Ngf), pleiotrophin (Ptn), and midkine (Mdk) in AD-Muse cells than in BM-Muse cells. To assess their anti-inflammatory effects in vitro, Muse cells and macrophages were co-cultured, and the levels of cytokines (tumor necrosis factor [TNF] α and interleukin [IL] 10) were measured in the medium. Consequently, we found that TNFα levels were lower in AD-Muse cells than in BM-Muse cells (p = 0.009), and IL10 levels were higher in AD-Muse cells than in BM-Muse cells (p = 0.008). Further, we induced moderate injuries via contusion of the spinal cord at the T10 level; Muse cells were transplanted intralesionally 7 days post-SCI. The number of surviving cells, alongside the number of CD86+ (M1 inflammatory effect), and CD206+ (M2 anti-inflammatory effect) macrophages in the spinal cord were measured 7 days post-transplantation. The number of surviving AD-Muse cells was higher than the number of surviving BM-Muse cells (ratio of AD-Muse/BM-Muse = 2.5, p > 0.05). The M1/M2 ratio in the AD-Muse cell-group (0.37) was lower than that in the control (phosphate-buffered saline) group (3.60, p = 0.008). The lesion area in the AD-Muse cell group was smaller than that in the BM-non-Muse (p = 0.049) and control groups (p = 0.012). As AD-Muse cells conferred a higher cell survival and neurotrophic factor secretion ability in vitro, AD-Muse cells demonstrated reduced inflammation after SCI. Overall, intralesional AD-Muse cell therapy is a potential therapeutic candidate that is expected to exhibit anti-inflammatory effects following acute SCI.

Spinal Cord Injury (SCI) is a devastating neurological disorder comprising primary mechanical injury and secondary inflammatory response-mediated injury for which an effective treatment is still unavailable. It is well known that secondary inflammatory responses are a significant cause of difficulties in neurological recovery. An immune imbalance between M1/M2 macrophages at the sites of injury is involved in developing and progressing the secondary inflammatory response. Recently, Mesenchymal Stem Cells (MSCs) have shown significant therapeutic potential in tissue engineering and regenerative medicine due to their potential multidirectional differentiation and immunomodulatory properties. Accumulating evidence shows that MSCs can regulate the balance of M1/M2 macrophage polarization, suppress downstream inflammatory responses, facilitate tissue repair and regeneration, and improve the prognosis of SCI. This article briefly overviews the impact of macrophages and MSCs on SCI and repair. It discusses the mechanisms by which MSCs regulate macrophage plasticity, including paracrine action, release of exosomes and apoptotic bodies, and metabolic reprogramming. Additionally, the article summarizes the relevant signaling pathways of MSCs that regulate macrophage polarization.

Liver fibrosis is a dynamic pathological process in which the structure and function of the liver abnormally change due to long-term complex inflammatory reactions and chronic liver injury caused by multiple internal and external factors. Previous studies believed that the activation of hepatic stellate cells is a critical part of the occurrence and development of liver fibrosis. However, an increasing number of studies have indicated that the macrophage plays an important role as a central regulator in liver fibrosis, and it directly affects the development and recovery of liver fibrosis. Studies of macrophages and liver fibrosis in the recent 10 years will be reviewed in this paper. This review will not only clarify the molecular mechanism of liver fibrosis regulated by macrophages but also provide new strategies and methods for ameliorating and treating liver fibrosis.

Spinal cord injury (SCI) is a devastating condition, often leading to significant disability and impairment. As crucial immune cells, macrophages play a critical role in the pathophysiology of SCI. Understanding the current state of knowledge and research trends related to macrophages in SCI is crucial for developing effective therapeutic interventions.

Using search strategies, we retrieved relevant articles from the Web of Science Core Collection (WOSCC), resulting in a robust dataset for analysis. VOSviewer, Citespace, and PRISM were employed for analysis and visualization. Various bibliometric indicators, including publication trends, citation analysis, co-authorship networks, and keyword analysis, were utilized to assess the scholarly landscape of macrophage research in SCI.

Our findings revealed a steady increase in publications over the past 33 years, indicating a growing interest in this field. We identified Popovich Phillip G was the most influential author, Ohio State University was the most influential institution, and identification of 2 distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord was the most influential paper in this field.

This bibliometric analysis provides a comprehensive overview of the current knowledge landscape and research trends regarding macrophages in SCI. Neuroinflammation and macrophage polarization, transplation and molecular mechanism were emerging research areas and novel directions. Our study serves as a valuable resource for researchers in spinal cord injury research and therapeutic development.

Spinal Cord Injury (SCI), with its morbidity characteristics of high disability rate and high mortality rate, is a disease that is highly destructive to both the physiology and psychology of the patient, and for which there is still a lack of effective treatment. Following spinal cord injury, a cascade of secondary injury reactions known as ischemia, peripheral inflammatory cell infiltration, oxidative stress, etc. create a microenvironment that is unfavorable to neural recovery and ultimately results in apoptosis and necrosis of neurons and glial cells. Mesenchymal stem cell (MSC) transplantation has emerged as a more promising therapeutic options in recent years. MSC can promote spinal cord injury repair through a variety of mechanisms, including immunomodulation, neuroprotection, and nerve regeneration, giving patients with spinal cord injury hope. In this paper, it is discussed the neuroprotection and nerve regeneration components of MSCs' therapeutic method for treating spinal cord injuries.

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.

Spinal cord injury is a traumatic lesion that causes a catastrophic condition in patients, resulting in neuronal deficit and loss of motor and sensory function. That loss is caused by secondary injury events following mechanical damage, which results in cell death. One of the most important events is inflammation, which activates molecules like proinflammatory cytokines (IL-1β, IFN-γ, and TNF-α) that provoke a toxic environment, inhibiting axonal growth and exacerbating CNS damage. As there is no effective treatment, one of the developed therapies is neuroprotection of the tissue to preserve healthy tissue. Among the strategies that have been developed are the use of cell therapy, the use of peptides, and molecules or supplements that have been shown to favor an anti-inflammatory environment that helps to preserve tissue and cells at the site of injury, thus favoring axonal growth and improved locomotor function. In this review, we will explain some of these strategies used in different animal models of spinal cord injury, their activity as modulators of the immune system, and the benefits they have shown.

Neurological disorders represent a global health problem. Current pharmacological treatments often lead to short-term symptomatic relief but have dose-dependent side effects, such as inducing orthostatic arterial hypotension due to the blockade of alpha receptors, cardiotoxic effects due to impaired repolarization, and atrioventricular block and tachycardia, including ventricular fibrillation. These challenges have driven the medical community to seek effective treatments for this serious global health threat. Mesenchymal stem cells (MSCs) are pluripotent cells with anti-inflammatory, anti-apoptotic, and immunomodulatory properties, providing a promising alternative due to their ability to differentiate, favorable culture conditions, in vitro manipulation ability, and robust properties. Although MSCs themselves rarely differentiate into neurons at the site of injury after transplantation in vivo, paracrine factors secreted by MSCs can create environmental conditions for cell-to-cell communication and have shown therapeutic effects. Recent studies have shown that the pleiotropic effects of MSCs, particularly their immunomodulatory potential, can be attributed primarily to these paracrine factors. Exosomes derived from MSCs are known to play an important role in these effects. Many studies have evaluated the potential of exosome-based therapies for the treatment of various neurological diseases. In addition to exosomes, various miRNAs derived from MSCs have been identified to regulate genes and alleviate neuropathological changes in neurodegenerative diseases. This review explores the burgeoning field of exosome-based therapies, focusing on the effects of MSC-derived exosomes and exosomal miRNAs, and summarizes recent findings that shed light on the potential of exosomes in the treatment of neurological disorders. The insights gained from this review may pave the way for innovative and effective treatments for these complex conditions. Furthermore, we suggest the therapeutic effects of exosomes and exosomal miRNAs from MSCs, which have a rescue potential in spinal cord injury via diverse signaling pathways.

Mesenchymal stromal cells (MSCs) administered intravenously (IV) have shown efficacy in preclinical models of various diseases. This is despite the cells not reaching the site of injury due to entrapment in the lungs. The immunomodulatory properties of MSCs are thought to underlie their therapeutic effects, irrespective of whether they are sourced from bone marrow, adipose tissue, or umbilical cord. To better understand how MSCs affect innate immune cell populations in the lung, we evaluated the distribution and phenotype of neutrophils, monocytes, and macrophages by flow cytometry and histological analyses after delivering human umbilical cord-derived MSCs (hUC-MSCs) IV into immunocompetent mice. After 2 hr, we observed a significant increase in neutrophils, and proinflammatory monocytes and macrophages. Moreover, these immune cells localized in close proximity to the MSCs, suggesting an active role in their clearance. By 24 hr, we detected an increase in anti-inflammatory monocytes and macrophages. These results suggest that the IV injection of hUC-MSCs leads to an initial inflammatory phase in the lung shortly after injection, followed by a resolution phase 24 hr later.

Spinal cord injury (SCI) is defined as traumatic damage to the spinal cord, affecting over three million patients worldwide, and there is still no treatment for the injured spinal cord itself. In recent years, immunology research on SCI has been published in various journals.

To systematically analyze the research hotspots and dynamic scientific developments of immunology research in SCI, we conducted a bibliometric and knowledge map analysis to help researchers gain a global perspective in this research field.

The bibliometric study we completed included 1788 English-language papers published in 553 journals by 8861 authors from 1901 institutions in 66 countries/regions. Based on the references and keyword analysis, researchers in the past 10 years have mainly focused on the research directions of "monocyte chemoattractor protein 1," "nitric oxide," "pain," and "nitric oxide synthase" related to immunological research in SCI. However, with the development of other new directions such as "extracellular vesicles" (2019-2022), "Regenerative medicine" (2019-2022), "stromal cells" (2018-2022), "motor recovery" (2019-2022), and "glial activation" (2019-2022). Researchers prefer to study the application of regenerative strategies in SCI, the mechanism of extracellular vesicles in the development of SCI, the activation of spinal glial cells in SCI, and the pathways of motor recovery. This bibliometric analysis of immunology research in SCI summarizes the current status of this research field. The relationship between extracellular vesicles, regenerative medicine, stromal cells, motor recovery, and glial activation is currently a major research frontier. Further research and cooperation worldwide need to be enhanced.

We believe that our research can help researchers quickly grasp the current hotspot of immunology research in SCI and determine a new direction for future research.

Radiation therapy is one of the most commonly used treatments for head and neck cancers, but it often leads to radiation-induced brain injury. Patients with radiation-induced brain injury have a poorer quality of life, and no effective treatments are available. The pathogenesis of this condition is unknown. This review summarizes the molecular biological mechanism of radiation-induced brain injury and provides research directions for future studies. The molecular mechanisms of radiation-induced brain injury are diverse and complex. Radiation-induced chronic neuroinflammation, destruction of the blood-brain barrier, oxidative stress, neuronal damage, and physiopathological responses caused by specific exosome secretion lead to radiation-induced brain injury.

Spinal cord injury (SCI) is a devastating condition that enormously affects an individual's health and quality of life. Neurogenic lower urinary tract dysfunction (NLUTD) is one of the most important sequelae induced by SCI, causing complications including urinary tract infection, renal function deterioration, urinary incontinence, and voiding dysfunction. Current therapeutic methods for SCI-induced NLUTD mainly target on the urinary bladder, but the outcomes are still far from satisfactory. Stem cell therapy has gained increasing attention for years for its ability to rescue the injured spinal cord directly. Stem cell differentiation and their paracrine effects, including exosomes, are the proposed mechanisms to enhance the recovery from SCI. Several animal studies have demonstrated improvement in bladder function using mesenchymal stem cells (MSCs) and neural stem cells (NSCs). Human clinical trials also provide promising results in urodynamic parameters after MSC therapy. However, there is still uncertainty about the ideal treatment window and application protocol for stem cell therapy. Besides, data on the therapeutic effects regarding NSCs and stem cell-derived exosomes in SCI-related NLUTD are scarce. Therefore, there is a pressing need for further well-designed human clinical trials to translate the stem cell therapy into a formal therapeutic option for SCI-induced NLUTD.

Accumulating evidence indicates that most primary Wharton's jelly mesenchymal stem cells (WJ-MSCs) therapeutic potential is due to their paracrine activity, i.e., their ability to modulate their microenvironment by releasing bioactive molecules and factors collectively known as secretome. These bioactive molecules and factors can either be released directly into the surrounding microenvironment or can be embedded within the membrane-bound extracellular bioactive nano-sized (usually 30-150 nm) messenger particles or vesicles of endosomal origin with specific route of biogenesis, known as exosomes or carried by relatively larger particles (100 nm-1 μm) formed by outward blebbing of plasma membrane called microvesicles (MVs); exosomes and MVs are collectively known as extracellular vesicles (EVs). The bioactive molecules and factors found in secretome are of various types, including cytokines, chemokines, cytoskeletal proteins, integrins, growth factors, angiogenic mediators, hormones, metabolites, and regulatory nucleic acid molecules. As expected, the secretome performs different biological functions, such as immunomodulation, tissue replenishment, cellular homeostasis, besides possessing anti-inflammatory and anti-fibrotic effects. This review highlights the current advances in research on the WJ-MSCs' secretome and its prospective clinical applications.

Spinal cord injury (SCI) remains a severe condition with an extremely high disability rate. The challenges of SCI repair include its complex pathological mechanisms and the difficulties of neural regeneration in the central nervous system. In the past few decades, researchers have attempted to completely elucidate the pathological mechanism of SCI and identify effective strategies to promote axon regeneration and neural circuit remodeling, but the results have not been ideal. Recently, new pathological mechanisms of SCI, especially the interactions between immune and neural cell responses, have been revealed by single-cell sequencing and spatial transcriptome analysis. With the development of bioactive materials and stem cells, more attention has been focused on forming intermediate neural networks to promote neural regeneration and neural circuit reconstruction than on promoting axonal regeneration in the corticospinal tract. Furthermore, technologies to control physical parameters such as electricity, magnetism and ultrasound have been constantly innovated and applied in neural cell fate regulation. Among these advanced novel strategies and technologies, stem cell therapy, biomaterial transplantation, and electromagnetic stimulation have entered into the stage of clinical trials, and some of them have already been applied in clinical treatment. In this review, we outline the overall epidemiology and pathophysiology of SCI, expound on the latest research progress related to neural regeneration and circuit reconstruction in detail, and propose future directions for SCI repair and clinical applications.

Spinal cord injury (SCI) is a destructive condition that results in lasting neurological damage resulting in disruption of the connection between the central nervous system and the rest of the body. Currently, there are several approaches in the treatment of a damaged spinal cord; however, none of the methods allow the patient to return to the original full-featured state of life before the injury. Cell transplantation therapies show great potential in the treatment of damaged spinal cords. The most examined type of cells used in SCI research are mesenchymal stromal cells (MSCs). These cells are at the center of interest of scientists because of their unique properties. MSCs regenerate the injured tissue in two ways: (i) they are able to differentiate into some types of cells and so can replace the cells of injured tissue and (ii) they regenerate tissue through their powerful known paracrine effect. This review presents information about SCI and the treatments usually used, aiming at cell therapy using MSCs and their products, among which active biomolecules and extracellular vesicles predominate.

Mesenchymal stromal cell transplantation alone is insufficient when motor dysfunction is severe; combination therapy with rehabilitation could improve motor function. Here, we aimed to analyze the characteristics of adipose-derived MSCs (AD-MSCs) and determine their effectiveness in severe spinal cord injury (SCI) treatment. A severe SCI model was created and motor function were compared. The rats were divided into AD-MSC-transplanted treadmill exercise-combined (AD-Ex), AD-MSC-transplanted non-exercise (AD-noEx), PBS-injected exercise (PBS-Ex), and no PBS-injected exercise (PBS-noEx) groups. In cultured cell experiments, AD-MSCs were subjected to oxidative stress, and the effects on the extracellular secretion of AD-MSCs were investigated using multiplex flow cytometry. We assessed angiogenesis and macrophage accumulation in the acute phase. Spinal cavity or scar size and axonal preservation were assessed histologically in the subacute phase. Significant motor function improvement was observed in the AD-Ex group. Vascular endothelial growth factor and C-C motif chemokine 2 expression in AD-MSC culture supernatants increased under oxidative stress. Enhanced angiogenesis and decreased macrophage accumulation were observed at 2 weeks post-transplantation, whereas spinal cord cavity or scar size and axonal preservation were observed at 4 weeks. Overall, AD-MSC transplantation combined with treadmill exercise training improved motor function in severe SCI. AD-MSC transplantation promoted angiogenesis and neuroprotection.

Spinal cord injury (SCI) represents a significant medical challenge, often resulting in permanent disability and severely impacting the quality of life for affected individuals. Traditional treatment options remain limited, underscoring the need for novel therapeutic approaches. In recent years, multipotent mesenchymal stem cells (MSCs) have emerged as a promising candidate for SCI treatment due to their multifaceted regenerative capabilities. This comprehensive review synthesizes the current understanding of the molecular mechanisms underlying MSC-mediated tissue repair in SCI. Key mechanisms discussed include neuroprotection through the secretion of growth factors and cytokines, promotion of neuronal regeneration via MSC differentiation into neural cell types, angiogenesis through the release of pro-angiogenic factors, immunomodulation by modulating immune cell activity, axonal regeneration driven by neurotrophic factors, and glial scar reduction via modulation of extracellular matrix components. Additionally, the review examines the various clinical applications of MSCs in SCI treatment, such as direct cell transplantation into the injured spinal cord, tissue engineering using biomaterial scaffolds that support MSC survival and integration, and innovative cell-based therapies like MSC-derived exosomes, which possess regenerative and neuroprotective properties. As the field progresses, it is crucial to address the challenges associated with MSC-based therapies, including determining optimal sources, intervention timing, and delivery methods, as well as developing standardized protocols for MSC isolation, expansion, and characterization. Overcoming these challenges will facilitate the translation of preclinical findings into clinical practice, providing new hope and improved treatment options for individuals living with the devastating consequences of SCI.

Ischemic damage to the central nervous system (CNS) is a catastrophic postoperative complication of aortic occlusion subsequent to cardiovascular surgery that can cause brain impairment and sometimes even paraplegia. Over recent years, numerous studies have investigated techniques for protecting and revascularizing the nervous system during intraoperative ischemia; however, owing to a lack of knowledge of the physiological distinctions between the brain and spinal cord, as well as the limited availability of testing techniques and treatments for ischemia-reperfusion injury, the cause of brain and spinal cord ischemia-reperfusion injury remains poorly understood, and no adequate response steps are currently available in the clinic. Given the limited ability of the CNS to repair itself, it is of great clinical value to make full use of the proliferative and differentiation potential of stem cells to repair nerves in degenerated and necrotic regions by stem cell transplantation or mobilization, thereby introducing a novel concept for the treatment of severe CNS ischemia-reperfusion injury. This review summarizes the most recent advances in stem cell therapy for ischemia-reperfusion injury in the brain and spinal cord, aiming to advance basic research and the clinical use of stem cell therapy as a promising treatment for this condition.