Spinal cord injuries lead to significant loss of motor, sensory, and autonomic functions, presenting major challenges in neural regeneration. Achieving effective therapeutic concentrations at injury sites has been a slow process, partly due to the difficulty of delivering drugs effectively. Nanoparticles, with their targeted delivery capabilities, biocompatibility, and enhanced bioavailability over conventional drugs, are garnering attention for spinal cord injury treatment. This review explores the current mechanisms and shortcomings of existing treatments, highlighting the benefits and progress of nanoparticle-based approaches. We detail nanoparticle delivery methods for spinal cord injury, including local and intravenous injections, oral delivery, and biomaterial-assisted implantation, alongside strategies such as drug loading and surface modification. The discussion extends to how nanoparticles aid in reducing oxidative stress, dampening inflammation, fostering neural regeneration, and promoting angiogenesis. We summarize the use of various types of nanoparticles for treating spinal cord injuries, including metallic, polymeric, protein-based, inorganic non-metallic, and lipid nanoparticles. We also discuss the challenges faced, such as biosafety, effectiveness in humans, precise dosage control, standardization of production and characterization, immune responses, and targeted delivery in vivo. Additionally, we explore future directions, such as improving biosafety, standardizing manufacturing and characterization processes, and advancing human trials. Nanoparticles have shown considerable progress in targeted delivery and enhancing treatment efficacy for spinal cord injuries, presenting significant potential for clinical use and drug development.

Combinatorial treatments integrating cells and biomolecules within scaffolds have been investigated to address the multifactorial nature of spinal cord injury (SCI). Current regenerative treatments have been ineffective as they do not consider the spatial positions of various cell types to effectively form functional neural pathways. Emulating the complex heterogeneity of cells in the native spinal cord requires translating the existing biological understanding of spatial patterning in neural development, as well as the influence of biomolecule and mechanical patterning on regional specification and axonal regeneration, to engineer a scaffold for spinal cord regeneration. This review explores the potential of 3D bioprinting to precisely control material, cell and drug patterns in scaffolds, achieving spatial phenotype specification and providing axonal guidance to form appropriate connections. We also discuss the application of extrusion-based and digital light processing bioprinting in integrating mechanical, chemical and biological cues within a scaffold to advance spatially patterned 3D bioprinted scaffold, as well as current challenges and future perspectives in these bioengineering strategies.

Mesenchymal stem cells advantageous properties have led scientists to conduct trials on a range of medical conditions, including incurable neurodegenerative diseases. Wharton-Jelly derived mesenchymal stem cells, given their ease of collection, are frequently selected for these studies. This research aimed to investigate the effects of nerve growth factor (NGF) gene overexpression on the neural differentiation, survivability, and gene and protein expression of these cells. The level of gene expression was tested using the ddPCR method. Six umbilical cords from donors were collected, and three randomly chosen primary cultures of Wharton-Jelly derived mesenchymal stem cells were used in experiment. Cells were transduced with lentiviral vectors and underwent a 12-day differentiation process. The results revealed neuron-like cells with significantly high expression of CHAT, GAD2 and TH genes. A corresponding increase in protein expression was also observed. Immunostaining demonstrated notable differences in neuron-like phenotypes, contingent on the environmental conditions of the research groups. Throughout the experiment, samples with transduced mesenchymal stem cells overexpressing the NGF gene showed the highest expression levels from almost all of studied genes and proteins, and were also the most phenotypically similar to neuron-like cells. The study concluded that sustained overexpression of NGF: guides mesenchymal stem cells towards the neural pathway, facilitates the differentiation of modified mesenchymal stem cells into GABAergic, dopaminergic, and cholinergic neuron-like cells, suggests that GABAergic neurons' marker predominantly co-expresses with other neurons' markers, such as cholinergic or dopaminergic ones, increases survivability of modified mesenchymal stem cells in toxic conditions; The limitations of the study is that we merely know that cells have begun to express neurogenic markers, but in the absence of standards for mature neuronal markers, we do not yet know how far they have progressed as differentiating cells.

In the central nervous system, cell-to-cell interaction is essential for brain plassticity and repair, and its alteration is critically involved in the development of neurodegenerative diseases. Neural stem cells are a plentiful source of biological signals promoting neuroplasticity and the maintenance of cognitive functions. Extracellular vesicles (EVs) represent an additional strategy for cells to release signals in the surrounding cellular environment or to exchange information among both neighboring and distant cells. In the last years, rising attention has been devoted to the ability of stem cell (SC)-derived EVs to counteract inflammatory and degenerative brain disorders taking advantage of their immunomodulatory capacities and regenerative potential. Here, we review the role of adult neurogenesis impairment in the cognitive decline associated with neurodegenerative diseases and describe the beneficial effects of SC-derived EVs on brain plasticity and repair also discussing the advantages of SC-derived EV administration vs SC transplantation in the treatment of neurodegenerative disorders.

To investigate the efficacy of intrathecal combined administration of autologous bone marrow-derived mesenchymal stem cells (BMSCs) and Schwann cells (SCs) in urinary function improvement in complete spinal cord injury (SCI) patients for the first time.

This study was a randomized phase II clinical trial, including treatment and control arms. Patients with traumatic complete SCI-induced neurogenic bladder were included. The treatment group received a single intrathecal combined injection of autologous BMSCs and SCs. The control group underwent no additional intervention. The outcome measures of the study were urodynamic study parameters, number of incontinence and urinary tract infection episodes, incontinence quality of life questionnaire, functional status, and sensorimotor improvements.

Among a total of 32 recruited patients, 13 and 16 were completely followed up in the treatment and control group, respectively. Changes in bladder compliance (P = 0.032), maximum pressure of detrusor during the filling phase (P = 0.013), maximum pressure of detrusor at the maximum urinary flow rate (P = 0.020), maximum urinary flow rate (P = 0.001), and postvoid residual volume (P = 0.001) after 6 months were significantly different between the 2 groups. The number of urinary incontinence episodes (P = 0.022) significantly reduced in the treatment group after 6 months compared with the baseline. The incontinence quality of life total and domain scores significantly improved in the treatment group compared with the control group after 6 months.

The combined intrathecal administration of BMSCs and SCs significantly improved the urodynamic study parameters, urinary incontinence rate, and incontinence quality of life in complete SCI-induced neurogenic bladder.

Tissue engineering provides a path forward for emerging personalized medicine therapies as well as the ability to bring about cures for diseases or chronic injuries. Traumatic spinal cord injuries (SCIs) are an example of a chronic injury in which no cure or complete functional recovery treatment has been developed. In part, this has been due to the complex and interconnected nature of the central nervous system (CNS), the cellular makeup, its extracellular matrix (ECM), and the injury site pathophysiology. One way to combat the complex nature of an SCI has been to create functional tissue-engineered scaffolds that replace or replenish the aspects of the CNS and tissue/ECM that are damaged following the immediate injury and subsequent immune response. This can be achieved by employing the tissue-engineering triad consisting of cells, biomaterial(s), and environmental factors. Stem cells, with their innate ability to proliferate and differentiate, are a common choice for cellular therapies. Natural or synthetic biomaterials that have tunable characteristics are normally used as the scaffold base. Environmental factors can range from drugs to growth factors (GFs) or proteins, depending on if the idea would be to stimulate exogeneous or endogenous cell populations or just simply retain cells on the scaffold for effective transplantation. For functional regeneration and integration for SCI, the scaffold must promote neuroprotection and neuroplasticity. Tissue-engineering strategies have shown benefits including neuronal differentiation, axonal regeneration, axonal outgrowth, integration into the native spinal cord, and partial functional recovery. Overall, this review focuses on the background that causes SCI to be so difficult to treat, the individual components of the tissue-engineering triad, and how combinatorial scaffolds can be beneficial toward the prospects of future SCI recovery.

Stem cell-based therapies have raised considerable interest to develop regenerative treatment for neurological disorders with high disability. In this review, we focus on recent preclinical and clinical evidence of stem cell therapy in the treatment of degenerative neurological diseases and discuss different cell types, delivery routes and biodistribution of stem cell therapy. In addition, recent advances of mechanistic insights of stem cell therapy, including functional replacement by exogenous cells, immunomodulation and paracrine effects of stem cell therapies are also demonstrated. Finally, we also highlight the adjunction approaches that has been implemented to augment their reparative function, survival and migration to target specific tissue, including stem cell preconditioning, genetical engineering, co-transplantation and combined therapy.

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.

Neuropathic pain is a debilitating complication following spinal cord injury (SCI). Currently, effective treatments for SCI-induced neuropathic pain are highly lacking. This clinical trial aimed to investigate the efficacy of combined intrathecal injection of Schwann cells (SCs) and bone marrow-derived mesenchymal stem cells (BMSCs) in improving SCI-induced neuropathic pain. This study was a parallel-group, randomized, open-label, active-controlled phase II trial with two arms, including treatment and control groups. Patients with complete SCI-induced neuropathic pain in the treatment group received a single combined intrathecal injection of BMSCs and SCs. Study outcome measures were International SCI Pain Basic Data Set (ISCIPBDS) and World Health Organization (WHO) Quality of Life Assessment Instrument (WHOQOL-BREF). A total of 37 (55.2%) and 30 (44.8%) patients in the treatment and control groups were followed up for 6 months, respectively. Significant reductions in mean scores of interference items in the treatment group, including daily activities (P < 0.001), mood (P < 0.001), and sleep (P < 0.001), were found at 6 months after the injection compared with the control one. Similarly, pain frequency (P = 0.002), mean (P = 0.001), and worst (P = 0.001) numeric rating scale (NRS) pain intensity scores showed significant reductions in the treatment group after 6 months compared with the control one. Based on multiple regression analysis controlled for potential confounders, significant associations between changes in all outcome measures over the study period and the treatment group were found. This clinical trial indicated the efficacy of combined cell therapy in improving the neuropathic pain and quality of life in complete SCI patients. Future investigations should evaluate the effects of combination of this strategy with other existing therapies for SCI-induced neuropathic pain. This clinical trial was also registered prospectively at the Iranian Registry of Clinical Trials (IRCT20200502047277N8).

Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, is a debilitating, incurable neurodegenerative disorder characterised by motor neuron death in the spinal cord, brainstem, and motor cortex. With an incidence rate of about 4.42 cases per 100,000 people annually, ALS severely impacts motor function and quality of life, causing progressive muscle atrophy, spasticity, paralysis, and eventually death. The cause of ALS is largely unknown, with 90% of cases being sporadic and 10% familial. Current research targets molecular mechanisms of inflammation, excitotoxicity, aggregation-prone proteins, and proteinopathy.

This review evaluates the efficacy of three stem cell types in ALS treatment: mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs).

MSCs, derived from various tissues, show neuroprotective and regenerative qualities, with clinical trials suggesting potential benefits but limited by small sample sizes and non-randomised designs. NSCs, isolated from the fetal spinal cord or brain, demonstrate promise in animal models but face functional integration and ethical challenges. iPSCs, created by reprogramming patient-specific somatic cells, offer a novel approach by potentially replacing or supporting neurons. iPSC therapy addresses ethical issues related to embryonic stem cells but encounters challenges regarding genotoxicity and epigenetic irregularities, somatic cell sources, privacy concerns, the need for extensive clinical trials, and high reprogramming costs.

This research is significant for advancing ALS treatment beyond symptomatic relief and modest survival extensions to actively modifying disease progression and improving patient outcomes. Successful stem cell therapies could lead to new ALS treatments, slowing motor function loss and reducing symptom severity.

Spinal cord injury (SCI) inflicts a severe burden on patients and lacks effective treatments. Owing to the poor regenerative capabilities of endogenous oligodendrocyte precursor cells (OPCs) following SCI, there is a growing interest in alternative sources, such as human umbilical cord mesenchymal stem cells (HUCMSCs). TET3 is a key DNA demethylase that plays an important role in neural differentiation, but its role in OPC formation is not well understood. This study aimed to explore the TET3-mediated one-step induction of HUCMSCs into OPCs.

In vitro, HUCMSCs were induced into OPCs following TET3 overexpression. Changes of methylation and hydroxymethylation during differentiation were monitored, mechanisms involved in the TET3-driven HUCMSC differentiation into OPCs were identified by RNA sequencing. Methylation levels in NG2 and PDGFRA promoter region were detected using Bisulfite Polymerase Chain Reaction (BSP).In vivo, therapeutic effects of iOPCs were evaluated through a rat Allen's SCI model.

The in vitro analysis confirmed that TET3 enhances HUCMSC differentiation into OPCs, validitied by specific marker expression. The induced OPCs (iOPCs) exhibited methylation and hydroxymethylation patterns similar to native OPCs. BSP analysis demonstrated that TET3 overexpression significantly reduced CpG island methylation in the NG2 and PDGFRA promoter regions. RNA sequencing revealed that TET3 induces iOPCs to express a series of genes essential for OPC formation while inhibiting the signaling pathways that hinder OPC development. In a rat model of SCI, TET3-overexpressing HUCMSCs appear to have the potential to differentiate into iOPCs in vivo, suppressed secondary injury, and promoted functional recovery. The therapeutic effects of iOPCs on SCI were superior to those of standard mesenchymal stem cell treatments.

Our study demonstrated that TET3-mediated demethylation reshapes the methylation patterns of HUCMSCs, enabling their efficient one-step conversion into OPCs and significantly reducing the time required for cell preparation. This approach offers a potential strategy for early intervention in SCI. In an SCI model, TET3-induced OPCs contributed to spinal cord repair, providing novel insights into cell therapy strategies for SCI through the lens of methylation regulation.

Dental pulp stem cells (DPSCs) show potential for treating neurodegenerative and traumatic diseases due to their neural crest origin. Melatonin (MT), an endogenous neurohormone with well-documented anti-inflammatory and antioxidant properties, has shown promising results with MSCs in terms of engraftment, proliferation, and neuronal differentiation in animal SCI models. However, the effects of melatonin preconditioning on human dental pulp stem cells (hDPSCs) for SCI treatment remain unclear. This study investigates the impact of melatonin preconditioning on hDPSCs engraftment, neural differentiation, and neurological function in rats with SCI. Forty-two male Sprague-Dawley rats were divided into six groups: Control, Sham, Model, Vehicle, Lesion Treatment A (SCI + hDPSCs), and Lesion Treatment B (SCI + MT-hDPSCs). After obtaining hDPSCs, stem cells were evaluated using flow cytometry. Cell viability was assessed using the MTT assay. SCI was induced in the Model, Vehicle, Lesion Treatment A, and Lesion Treatment B groups. The Lesion Treatment A and B groups received hDPSCs and hDPSCs pretreated with melatonin, respectively, 1 week after SCI, while the Vehicle group received only an intravenous injection of DMEM to simulate treatment. The other groups were used for behavioral testing. Immunohistochemistry (IHC) was employed to assess hDPSCs engraftment and differentiation at the SCI site. Motor function across the six groups was evaluated using the Basso, Beattie, and Bresnahan (BBB) score. Histological studies and cell counts confirmed hDPSCs implantation at the injury site, with a significantly higher presence in the MT-hDPSCs compared to hDPSCs (p < 0.01). IHC revealed that hDPSCs and MT-hDPSCs differentiated into neurons and astrocytes, with greater differentiation observed in the MT-hDPSCs compared to the hDPSCs (p < 0.01 and p < 0.05, respectively). Functional improvement was noted in both SCI + hDPSCs and SCI + MT-hDPSCs groups compared to SCI and Vehicle groups from Week 4 onward (p < 0.001). Significant differences were also observed between the SCI + hDPSCs and SCI + MT-hDPSCs groups starting from Week 7 (p < 0.01). Preconditioning hDPSCs with melatonin enhances engraftment, neuronal differentiation, and greater performance improvement compared to hDPSCs alone in the SCI animal model.

Transplanted mesenchymal stem cells (MSCs) can significantly aid in repairing spinal cord injuries (SCIs) by migrating to and settling at the injury site. However, this process is typically inefficient, as only a small fraction of MSCs successfully reach the target lesion area. During SCI, the increased expression and secretion of hepatocyte growth factor (HGF) act as a chemoattractant that guides MSC migration. Nonetheless, the precise mechanisms by which HGF influences MSC migration are not fully understood. This study focused on unraveling the molecular pathways that drive MSC migration toward the SCI site in response to HGF. It was found that HGF can activate β-catenin signaling in MSCs by either phosphorylating LRP6, suppressing GSK3β phosphorylation through the AKT and ERK1/2 pathways, or enhancing the expression and nuclear translocation of TCF4. This activation leads to elevated Nedd9 expression, which promotes focal adhesion formation and F-actin polymerization, facilitating chemotactic migration. Transplanting MSCs during peak HGF expression in injured tissues substantially improves nerve regeneration, reduces scarring, and enhances hind limb mobility. Additionally, prolonging HGF release can further boost MSC migration and engraftment, thereby amplifying regenerative outcomes. However, inhibiting HGF/Met or interfering with β-catenin or Nedd9 signaling significantly impairs MSC engraftment, obstructing tissue repair and functional recovery. Together, these findings provide a theoretical basis and practical strategy for MSC transplantation therapy in SCI, highlighting the specific molecular mechanisms by which HGF regulates β-catenin signaling in MSCs, ultimately triggering their chemotactic migration.

Spinal cord injury (SCI) is damage to the spinal cord that permanently or temporarily disrupts its function, causing considerable autonomic, sensory, and motor disorders, and involves between 10 and 83 cases per million yearly. Traumatic SCI happens following primary acute mechanical damage, leading to injury to the spinal cord tissue and worsening clinical outcomes. The present therapeutic strategies for this complex disease fundamentally rely on surgical approaches and conservative remedies. However, these modalities are not effective enough for neurological recovery. Therefore, it is necessary to discover more efficient methods to treat patients with SCI. Today, considerable attention has been drawn to bioactive compounds-based remedies and stem cell therapy for curing various ailments and disorders, such as neurological diseases. Some researchers have recommended that harnessing curcumin, a polyphenol obtained from turmeric, in combination with stem cells, like mesenchymal stem cells, neural stem cells, and ependymal stem cells, can remarkably improve neurological recovery-related parameters more effective than the treatment with these two methods separately in experimental models. Hereby, this literature review delves into the functionality of curcumin combined with stem cells in treating SCI with a focus on cellular and molecular mechanisms.

Mesenchymal stem/stromal cells (MSC) play a pivotal role in regenerative therapies. Recent studies show that factors secreted by MSC can replicate their biological activity, driving the emergence of cell-free therapy, likely to surpass stem cell therapy. Patents are an objective measure of R&D and innovation activities, and patent mapping allows us to verify the state of the art and technology, anticipate trends, and identify emerging lines of research. This review performed a search on Derwent World Patents Index™ and retrieved 269 patent families related to the MSC-derived cell-free products. Analysis reveals an exponential increase in patents from the mid-2010s, primarily focusing on exosomes. The patent's contents offer a great diversity of applications and associated technologies by using the products as medicinal agents or drug delivery systems. Nevertheless, numerous application branches remain unexplored, suggesting vast potential for cell-free technologies alone or combined with other approaches.

Inflammation and stem cell mobilization or homing play pivotal roles in tissue repair and regeneration. This review explores their intricate interplay, elucidating their collaborative role in maintaining tissue homeostasis and responding to injury or disease. While examining the fundamentals of stem cells, we detail the mechanisms underlying inflammation, including immune cell recruitment and inflammatory mediator release, highlighting their self-renewal and differentiation capabilities. Central to our exploration is the modulation of hematopoietic stem cell behavior by inflammatory cues, driving their mobilization from the bone marrow niche into circulation. Key cytokines, chemokines, growth factors, and autophagy, an intracellular catabolic mechanism involved in this process, are discussed alongside their clinical relevance. Furthermore, mesenchymal stem cell homing in response to inflammation contributes to tissue repair processes. In addition, we discuss stem cell resilience in the face of inflammatory challenges. Moreover, we examine the reciprocal influence of stem cells on the inflammatory milieu, shaping immune responses and tissue repair. We underscore the potential of targeting inflammation-induced stem cell mobilization for regenerative therapies through extensive literature analysis and clinical insights. By unraveling the complex interplay between inflammation and stem cells, this review advances our understanding of tissue repair mechanisms and offers promising avenues for clinical translation in regenerative medicine.

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.

Neurological and functional impairments are commonly observed in individuals with spinal cord injury (SCI) due to insufficient regeneration of damaged axons. Exosomes play a crucial role in the paracrine effects of mesenchymal stem cells (MSCs) and have emerged as a promising therapeutic approach for SCI. Thus, this study aimed to evaluate the safety and potential effects of intrathecal administration of allogeneic exosomes derived from human umbilical cord MSCs (HUC-MSCs) in patients with complete subacute SCI.

This study was a single-arm, open-label, phase I clinical trial with a 12-month follow-up period. HUC-MSCs were extracted from human umbilical cord tissue, and exosomes were isolated via ultracentrifugation. After intrathecal injection, each participant a underwent complete evaluation, including neurological assessment using the American Spinal Injury Association (ASIA) scale, functional assessment using the Spinal Cord Independence Measure (SCIM-III), neurogenic bowel dysfunction (NBD) assessment using the NBD score, modified Ashworth scale (MAS), and lower urinary tract function questionnaire.

Nine patients with complete subacute SCI were recruited. The intrathecal injection of allogeneic HUC-MSCs-exosomes was safe and well tolerated. No early or late adverse event (AE) attributable to the study intervention was observed. Significant improvements in ASIA pinprick (P-value = 0.039) and light touch (P-value = 0.038) scores, SCIM III total score (P-value = 0.027), and NBD score (P-value = 0.042) were also observed at 12-month after the injection compared with baseline.

This study demonstrated that intrathecal administration of allogeneic HUC-MSCs-exosomes is safe in patients with subacute SCI. Moreover, it seems that this therapy might be associated with potential clinical and functional improvements in these patients. In this regard, future larger phase II/III clinical trials with adequate power are highly required.

Iranian Registry of Clinical Trials, IRCT20200502047277N1. Registered 2 October 2020, https://en.irct.ir/trial/48765 .

Mesenchymal Stromal Cells (MSCs) offer tremendous potential for the treatment of various diseases and their healing properties have been explored in hundreds of clinical trials. These trails primarily focus on immunological and neurological disorders, as well as regenerative medicine. Adipose tissue is a rich source of mesenchymal stromal cells and methods to obtain and culture adipose-derived MSCs (AD-MSCs) have been well established. Promising results from pre-clinical testing of AD-MSCs activity prompted clinical trials that further led to the approval of AD-MSCs for the treatment of complex perianal fistulas in Crohn's disease and subcutaneous tissue defects. However, AD-MSC heterogeneity along with various manufacturing protocols or different strategies to boost their activity create the need for standardized quality control procedures and safety assessment of the intended cell product. High-resolution transcriptomic methods have been recently gaining attention, as they deliver insight into gene expression profiles of individual cells, helping to deconstruct cellular hierarchy and differentiation trajectories, and to understand cell-cell interactions within tissues. This article presents a comprehensive overview of completed clinical trials evaluating the safety and efficacy of AD-MSC treatment, together with current single-cell studies of human AD-MSC. Furthermore, our work emphasizes the increasing significance of single-cell research in elucidating the mechanisms of cellular action and predicting their therapeutic effects.

Walking ability is a crucial factor for recovery and rehabilitation of spinal cord injury (SCI) patients.

The aim of this study was to investigate the effect of 12 weeks of rebound therapy on walking parameters in SCI patients.

Thirty members of Isfahan Spinal Cord Injury Association participated in this experimental study using a convenience sampling method. This study was approved by the ethics committee of the University of Isfahan (IR.UI.REC.1400.118). The participants were randomly assigned to control and rebound groups using a matched randomization method. Data were collected before and after 12 weeks of rebound therapy exercise (three sessions per week) in the walking laboratory, using a seven-camera 3D motion capturing system (Qualisys motion analysis). The final data were analyzed using repeated measures ANOVA in SPSS software (significance level p < .05).

Rebound therapy training significantly improved all dependent variables (p < .05) except hip rotation, indicating its effectiveness for enhancing walking ability.

Given the importance of walking function, we recommend the use of rebound therapy training as an exercise rehabilitation method for spinal cord injury patients.

This study aims to systematically evaluate the efficacy of bone marrow mesenchymal stem cell-derived exosomes (BMSCs-Exo) in improving spinal cord injury (SCI) to mitigate the risk of translational discrepancies from animal experiments to clinical applications.

We conducted a comprehensive literature search up to March 2024 using PubMed, Embase, Web of Science, and Scopus databases. Two researchers independently screened the literature, extracted data, and assessed the quality of the studies. Data analysis was performed using STATA16 software.

A total of 30 studies were included. The results indicated that BMSCs-Exo significantly improved the BBB score in SCI rats (WMD = 3.47, 95% CI [3.31, 3.63]), inhibited the expression of the pro-inflammatory cytokine TNF-α (SMD = -3.12, 95% CI [-3.57, -2.67]), and promoted the expression of anti-inflammatory cytokines IL-10 (SMD = 2.76, 95% CI [1.88, 3.63]) and TGF-β (SMD = 3.89, 95% CI [3.02, 4.76]). Additionally, BMSCs-Exo significantly reduced apoptosis levels (SMD = -4.52, 95% CI [-5.14, -3.89]), promoted the expression of axonal regeneration markers NeuN cells/field (SMD = 3.54, 95% CI [2.65, 4.42]), NF200 (SMD = 4.88, 95% CI [3.70, 6.05]), and the number of Nissl bodies (SMD = 1.89, 95% CI [1.13, 2.65]), and decreased the expression of astrogliosis marker GFAP (SMD = -5.15, 95% CI [-6.47, -3.82]). The heterogeneity among studies was primarily due to variations in BMSCs-Exo transplantation doses, with efficacy increasing with higher doses.

BMSCs-Exo significantly improved motor function in SCI rats by modulating inflammatory responses, reducing apoptosis, inhibiting astrogliosis, and promoting axonal regeneration. However, the presence of selection, performance, and detection biases in current animal experiments may undermine the quality of evidence in this study.

Alzheimer's disease (AD) is a condition in the brain that is marked by a gradual and ongoing reduction in memory, thought, and the ability to perform simple tasks. AD has a poor prognosis but no cure yet. Therefore, the need for novel models to study its pathogenesis and therapeutic strategies is evident, as the brain poorly recovers after injury and neurodegenerative diseases and can neither replace dead neurons nor reinnervate target structures. Recently, mesenchymal stem cells (MSCs), particularly those from the human olfactory mucous membrane referred to as the olfactory ecto-MSCs (OE-MSCs), have emerged as a potential avenue to explore in modeling AD and developing therapeutics for the disease due to their lifelong regeneration potency and facile accessibility. This review provides a comprehensive summary of the current literature on isolating OE-MSCs and delves into whether they could be reliable models for studying AD pathogenesis. It also explores whether healthy individual-derived OE-MSCs could be therapeutic agents for the disease. Despite being a promising tool in modeling and developing therapies for AD, some significant issues remain, which are also discussed in the review.

Stem cell-based therapies have emerged as a promising approach for treating various neurological disorders by harnessing the regenerative potential of stem cells to restore damaged neural tissue and circuitry. This comprehensive review provides an in-depth analysis of the current state of stem cell applications in primary neurological conditions, including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, spinal cord injury (SCI), and other related disorders. The review begins with a detailed introduction to stem cell biology, discussing the types, sources, and mechanisms of action of stem cells in neurological therapies. It then critically examines the preclinical evidence from animal models and early human trials investigating the safety, feasibility, and efficacy of different stem cell types, such as embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs). While ESCs have been studied extensively in preclinical models, clinical trials have primarily focused on adult stem cells such as MSCs and NSCs, as well as iPSCs and their derivatives. We critically assess the current state of research for each cell type, highlighting their potential applications and limitations in different neurological conditions. The review synthesizes key findings from recent, high-quality studies for each neurological condition, discussing cell manufacturing, delivery methods, and therapeutic outcomes. While the potential of stem cells to replace lost neurons and directly reconstruct neural circuits is highlighted, the review emphasizes the critical role of paracrine and immunomodulatory mechanisms in mediating the therapeutic effects of stem cells in most neurological disorders. The article also explores the challenges and limitations associated with translating stem cell therapies into clinical practice, including issues related to cell sourcing, scalability, safety, and regulatory considerations. Furthermore, it discusses future directions and opportunities for advancing stem cell-based treatments, such as gene editing, biomaterials, personalized iPSC-derived therapies, and novel delivery strategies. The review concludes by emphasizing the transformative potential of stem cell therapies in revolutionizing the treatment of neurological disorders while acknowledging the need for rigorous clinical trials, standardized protocols, and multidisciplinary collaboration to realize their full therapeutic promise.

Exosomes generated from adipose-derived mesenchymal stem cells (Exos), and in particular hypoxia-pretreated ADSCs (HExos), possess therapeutic properties that promote spinal cord repair following spinal cord injury (SCI). Nevertheless, the regulatory mechanisms through which HExos exert their effects remain unclear.

Here, next-generation sequencing (NGS) was utilized to examine abnormal circRNA expression comparing HExos to Exos. Bioinformatics analysis and RNA pulldown assays together with luciferase reporter assays were applied to determine interactions among miRNAs, mRNAs and circRNAs. ELISA and immunofluorescence staining were used to examine inflammatory cytokine levels, apoptosis and ROS deposition in LPS-treated HT-22 cells, respectively. The therapeutic effects of Exos and HExos on a mouse model of SCI were analyzed by immunohistochemistry and immunofluorescence staining.

Our findings confirmed that HExos have more significant therapeutic influences on decreasing ROS and inflammatory cytokine levels post-SCI than Exos. NGS revealed that circ-Wdfy3 expression levels were significantly higher in HExos than Exos. Downregulation of circ-Wdfy3 led to a decrease in HExo-induced therapeutic effects on spinal cord repair post-SCI, indicating that circ-Wdfy3 has a critical role in the regulation of HExo-mediated protection against SCI. Our bioinformatics, RNA pulldown and luciferase reporter data demonstrated that GPX4 and miR-423-3p were downstream targets of circ-Wdfy3. GPX4 downregulation or miR-423-3p overexpression reversed the protective effects of circ-Wdfy3 on LPS-treated HT-22 cells. Furthermore, overexpression of circ-Wdfy3 led to an in increase in the Exo-induced therapeutic effects on spinal cord repair post-SCI through the inhibition of ferroptosis.

circ-WDfy3-overexpressing Exos promote spinal cord repair post-SCI through mediation of ferroptosis via the miR-138-5p/GPX4 pathway.

Disruption of the blood-central nervous system barrier (BCB) is increasingly recognized as a pathological factor in diseases and trauma of the central nervous system. Despite the neuropathological impact, current treatment modalities do not target the BCB; strategies to reconstitute the impaired BCB have been restricted to nutritional and dietary remedies. As an integral cell type in the neurovascular unit, pericytes are crucial to the development, maintenance, and repair of the BCB. As such, pericytes are well poised as cellular agents for reconstitution of the impaired BCB. Here, we summarize recent revelations regarding the role of BCB disruption in diseases and trauma of the central nervous system and highlight how pericytes are harnessed to provide targeted therapeutic effect in each case. This review will also address how recent advances in pericyte derivation strategies can serve to overcome practical hurdles in the clinical use of pericytes.

Syringomyelia is a progressive chronic disease that leads to nerve pain, sensory dissociation, and dyskinesia. Symptoms often do not improve after surgery. Stem cells have been widely explored for the treatment of nervous system diseases due to their immunoregulatory and neural replacement abilities.

In this study, we used a rat model of syringomyelia characterized by focal dilatation of the central canal to explore an effective transplantation scheme and evaluate the effect of mesenchymal stem cells and induced neural stem cells for the treatment of syringomyelia.

The results showed that cell transplantation could not only promote syrinx shrinkage but also stimulate the proliferation of ependymal cells, and the effect of this result was related to the transplantation location. These reactions appeared only when the cells were transplanted into the cavity. Additionally, we discovered that cell transplantation transformed activated microglia into the M2 phenotype. IGF1-expressing M2 microglia may play a significant role in the repair of nerve pain.

Cell transplantation can promote cavity shrinkage and regulate the local inflammatory environment. Moreover, the proliferation of ependymal cells may indicate the activation of endogenous stem cells, which is important for the regeneration and repair of spinal cord injury.

Mesenchymal/medicinal stem/signaling cells (MSCs) have emerged as a promising treatment option for various disorders. However, the donor's age, advanced stage of disease, and prolonged in vitro expansion often diminish the innate regenerative potential of MSCs. Besides that, the absence of MSCs' comprehensive "pre-admission testing" can result in the injection of cells with reduced viability and function, which may negatively affect the overall outcome of MSC-based therapies. It is, therefore, essential to develop effective strategies to improve the impaired biological performance of MSCs. This review focuses on the comprehensive characterization of various methods of external MSCs stimulation (hypoxia, heat shock, caloric restriction, acidosis, 3D culture, and application of extracellular matrix) that augment their medicinal potential. To emphasize the significance of MSCs priming, we summarize the effects of individual and combined preconditioning approaches, highlighting their impact on MSCs' response to either physiological or pathological conditions. We further investigate the synergic action of exogenous factors to maximize MSCs' therapeutic potential. Not to omit the field of tissue engineering, the application of pretreated MSCs seeded on scaffolds is discussed as well.

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.

The therapeutic benefits of exosomes obtained from mesenchymal stem cells (MSCs) in acute spinal cord injury (SCI) have been demonstrated in recent years, but the precise mechanisms remain unknown. In this study, the efficacy and mechanisms of MSC-derived exosomes (MSC-Exo) in acute SCI were investigated.

By utilizing a BV2 ferroptosis cellular model and an SCI rat model, we investigated the effects of MSC-Exo on iron death related indicators and NF-E2 related factor 2 (Nrf2)/GTP cyclolase I (GCH1)/5,6,7,8-tetrahydrobiopterin (BH4) signaling axis, as well as their therapeutic effects on SCI rats.

The results revealed that MSC-Exo effectively inhibited the production of ferrous iron, lipid peroxidation products malonaldehyde and reactive oxygen species, and ferroptosis-promoting factor prostaglandin-endoperoxide synthase 2. Concurrently, they upregulated ferroptosis suppressors FTH-1 (ferritin heavy chain 1), SLC7A11 (solute carrier family 7 member 11), FSP1 (ferroptosis suppressor protein 1), and GPX4 (glutathione peroxidase 4), contributing to enhanced neurological recovery in SCI rats. Further analysis showed the Nrf2/GTP/BH4 signaling pathway's critical role in suppressing ferroptosis. Additionally, MSC-Exo was found to inhibit lipopolysaccharide-induced ferroptosis in BV2 cells and SCI rats by activating the Nrf2/GCH1/BH4 axis.

In summary, the study demonstrates that MSC-Exo mitigates microglial cell ferroptosis via the Nrf2/GCH1/BH4 axis, showing potential for preserving and restoring neurological function post-SCI.

Spinal cord injury (SCI) is a life-altering condition that severely impacts an individual's functional capabilities and has significant implications for both the individual and society. Large animal models are crucial for understanding the pathology and biomechanics of SCI. Dogs (Canis lupus familiaris) are promising models for SCI research due to their anatomical and histopathological similarities to humans. Balloon compression is an established method for inducing controlled SCI in canines. In this study, we optimized a balloon compression procedure for inducing SCI in dogs, aiming to develop a reliable model for future in vivo studies. Our methodology successfully induced total motoric loss in canines, observed for seven days, a critical period for therapeutic interventions. Histopathological examinations using Luxol fast blue (LFB) staining revealed total demyelination in intralesional samples, confirming the structural damage caused by balloon compression. We concluded that a balloon compression model at the T10-T11 vertebral level, with an inflated balloon volume of 1.0 ml, induced SCI while minimizing the risk of balloon rupture. Longer duration of compression ensures total paralysis in this model, providing a platform for testing therapeutic interventions during the acute phase of SCI. The canine model generated consistent data and facilitated straightforward observational findings.

Spinal cord injury (SCI) leads to significant destruction of nerve tissue, causing the degeneration of axons and the formation of cystic cavities. This study aimed to examine the characteristics of human umbilical cord-derived mesenchymal stem cells (HUCMSCs) cultured in a serum-free conditioned medium (CM) and assess their effectiveness in a well-established hemitransection SCI model.

In this study, HUCMSCs cultured medium was collected and characterized by measuring IL-10 and identifying proteomics using mass spectroscopy. This collected serum-free CM was further used in the experiments to culture and characterize the HUMSCs. Later, neuronal cells derived from CM-enriched HUCMSC were tested sequentially using an injectable caffeic acid-bioconjugated gelatin (CBG), which was further transplanted in a hemitransection SCI model. In vitro, characterization of CM-enriched HUCMSCs and differentiated neuronal cells was performed using flow cytometry, immunofluorescence, electron microscopy, and post-transplant analysis using immunohistology analysis, qPCR, in vivo bioluminescence imaging, and behavioral analysis using an infrared actimeter.

The cells that were cultured in the conditioned media produced a pro-inflammatory cytokine called IL-10. Upon examining the secretome of the conditioned media, the Kruppel-like family of KRAB and zinc-finger proteins (C2H2 and C4) were found to be activated. Transcriptome analysis also revealed an increased expression of ELK-1, HOXD8, OTX2, YY1, STAT1, ETV7, and PATZ1 in the conditioned media. Furthermore, the expression of Human Stem-101 confirmed proliferation during the first 3 weeks after transplantation, along with the migration of CBG-UCNSC cells within the transplanted area. The gene analysis showed increased expression of Nestin, NeuN, Calb-2, Msi1, and Msi2. The group that received CBG-UCNSC therapy showed a smooth recovery by the end of week 2, with most rats regaining their walking abilities similar to those before the spinal cord injury by week 5.

In conclusion, the CBG-UCNSC method effectively preserved the integrity of the transplanted neuronal-like cells and improved locomotor function. Thus, CM-enriched cells can potentially reduce biosafety risks associated with animal content, making them a promising option for clinical applications in treating spinal cord injuries.

Introduction: The purpose of this study is to achieve a significant increase in the proliferative activity of mesenchymal stem cells (MSCs) of the bone marrow (BM) at early passages after laser exposure to a suspension of these cells and to estimate the effect of light and heat components of laser radiation on the proliferation of BM MSCs. Methods: The studies were performed on rats BM MSCs. MSC suspension was placed into the wells and heated by using laser radiation (980 nm wavelength) or a water bath at 70 °C providing similar temperature dynamics. The studies were carried out in 3 comparison groups: (1) control suspension of MSCs, which was not subjected to heating in a water bath or laser exposure; (2) MSC suspension, which was heated for in a water bath; and (3) suspension of MSCs, which was subjected to laser exposure. The exposure times for the 2nd and 3rd experimental groups were 10- 50 seconds. Results: Under optimal parameters of laser action on the suspension of BM MSCs, a six-fold increase in the number of BM MSCs colonies was registered compared to the control. The role of the light and heat components of laser exposure to MSCs was determined by comparable heating of a suspension of BM MSCs in a water bath, at which only a twofold increase in the number of colonies was maximally obtained. Conclusion: The increase in the MSC proliferation activity occurs due to their Thermo-Photobiomodulation. The result obtained is important for practical use in cell transplantation in the treatment of traumatic injuries of bone, cartilage, and tendon tissues when a rapid and multiple increase in the initial number of autologous BM MSCs is required.

Traumatic spinal cord injury (TSCI) is a prevalent central nervous system condition that imposes a significant burden on both families and society, affecting more than 2 million people worldwide. Recently, there has been increasing interest in bone marrow mesenchymal stem cell (BMSC) transplantation as a promising treatment for spinal cord injury (SCI) due to their accessibility and low immunogenicity. However, the mere transplantation of BMSCs has limited capacity to directly participate in the repair of host spinal cord nerve function. MiR-28-5p, identified as a key differentially expressed miRNA in spinal cord ischemia-reperfusion injury, exhibits differential expression and regulation in various neurological diseases. Nevertheless, its involvement in this process and its specific regulatory mechanisms in SCI remain unclear. Therefore, this study aimed to investigate the potential mechanisms through which miR-28-5p promotes the neuronal differentiation of BMSCs both in vivo and in vitro. Our results indicate that miR-28-5p may directly target Notch1, thereby facilitating the neuronal differentiation of BMSCs in vitro. Furthermore, the transplantation of lentivirus-mediated miR-28-5p-overexpressed BMSCs into SCI rats effectively improved footprint tests and Basso, Beattie, and Bresnahan (BBB) scores, ameliorated histological morphology (hematoxylin-eosin [HE] and Nissl staining), promoted axonal regeneration (MAP2 and growth-associated protein 43 [GAP43]), and facilitated axonal remyelination (myelin basic protein [MBP]). These findings may suggest that miR-28-5p-modified BMSCs could serve as a therapeutic target to enhance the behavioral and neurological recovery of SCI rats.

The mainstay of treatment for spinal cord injury includes decompressive laminectomy and elevation of mean arterial pressure. However, outcomes often remain poor. Extensive research and ongoing clinical trials seek to design new treatment options for spinal cord injury, including stem cell therapy, scaffolds, brain-spine interfaces, exoskeletons, epidural electrical stimulation, ultrasound, and cerebrospinal fluid drainage. Some of these treatments are targeted at the initial acute window of injury, during which secondary damage occurs; others are designed to help patients living with chronic injuries.

Spinal cord injury (SCI) is a serious clinical condition that has pathological changes such as increased neuroinflammation and nerve tissue damage, which eventually manifests as fibrosis of the injured segment and the development of a spinal cord cavity leading to loss of function. Cell-based therapy, such as mesenchymal stem cells (MSCs) and neural stem cells (NSCs) are promising treatment strategies for spinal cord injury via immunological regulation and neural replacement respectively. However, therapeutic efficacy is rare reported on combined transplantation of MSC and NSC in acute mice spinal cord injury even the potential reinforcement might be foreseen. Therefore, this study was conducted to investigate the safety and efficacy of co-transplanting of MSC and NSC sheets into an SCI mice model on the locomotor function and pathological changes of injured spinal cord.

To evaluate the therapeutic effects of combination cells, acute SCI mice model were established and combined transplantation of hiPSC-NSCs and hMSCs into the lesion site immediately after the injury. Basso mouse scale was used to perform the open-field tests of hind limb motor function at days post-operation (dpo) 1, 3, 5, and 7 after SCI and every week after surgery. Spinal cord and serum samples were collected at dpo 7, 14, and 28 to detect inflammatory and neurotrophic factors. Hematoxylin-eosin (H&E) staining, masson staining and transmission electron microscopy were used to evaluate the morphological changes, fibrosis area and ultrastructure of the spinal cord.

M&N transplantation reduced fibrosis formation and the inflammation level while promoting the secretion of nerve growth factor and brain-derived neurotrophic factor. We observed significant reduction in damaged tissue and cavity area, with dramatic improvement in the M&N group. Compared with the Con group, the M&N group exhibited significantly improved behaviors, particularly limb coordination.

Combined transplantation of hiPSC-NSC and hMSC could significantly ameliorate neuroinflammation, promote neuroregeneration, and decrease spinal fibrosis degree in safe and effective pattern, which would be indicated as a novel potential cell treatment option.

Spinal cord injury (SCI) is a highly debilitating condition that inflicts devastating harm on the lives of affected individuals, underscoring the urgent need for effective treatments. By activating inflammatory cells and releasing inflammatory factors, the secondary injury response creates an inflammatory microenvironment that ultimately determines whether neurons will undergo necrosis or regeneration. In recent years, mesenchymal stem cells (MSCs) have garnered increasing attention for their therapeutic potential in SCI. MSCs not only possess multipotent differentiation capabilities but also have homing abilities, making them valuable as carriers and mediators of therapeutic agents. The inflammatory microenvironment induced by SCI recruits MSCs to the site of injury through the release of various cytokines, chemokines, adhesion molecules, and enzymes. However, this mechanism has not been previously reported. Thus, a comprehensive exploration of the molecular mechanisms and cellular behaviors underlying the interplay between the inflammatory microenvironment and MSC homing is crucial. Such insights have the potential to provide a better understanding of how to harness the therapeutic potential of MSCs in treating inflammatory diseases and facilitating injury repair. This review aims to delve into the formation of the inflammatory microenvironment and how it influences the homing of MSCs.

Spinal cord injuries (SCI) lead to functional alteration with important consequences such as motor and sensory disorders. The repair strategies developed to date remain ineffective. The adipose tissue-derived stromal vascular fraction (SVF) is composed of a cocktail of cells with trophic, pro-angiogenic and immunomodulatory effects. Numerous therapeutic benefits were shown for tissue reconstitution, peripheral neuropathy and for the improvement of neurodegenerative diseases. Here, the therapeutic efficacy of SVF on sensorimotor recovery after an acute thoracic spinal cord contusion in adult rats was determined.

Male Sprague Dawley rats (n = 45) were divided into 3 groups: SHAM (without SCI and treatment), NaCl (animals with a spinal lesion and receiving a saline injection through the dura mater) and SVF (animals with a spinal lesion and receiving a fraction of fat removed from adipocytes through the dura mater). Some animals were sacrificed 14 days after the start of the experiment to determine the inflammatory reaction by measuring the interleukin-1β, interleukin-6 and Tumor Necrosis Factor-α in the lesion area. Other animals were followed once a week for 12 weeks to assess functional recovery (postural and locomotor activities, sensorimotor coordination). At the end of this period, spinal reflexivity (rate-dependent depression of the H-reflex) and physiological adjustments (ventilatory response to metabosensitive muscle activation following muscle fatigue) were measured with electrophysiological tools.

Compared to non-treated animals, results indicated that the SVF reduced the endogenous inflammation and increased the behavioral recovery in treated animals. Moreover, H-reflex depression and ventilatory adjustments to muscle fatigue were found to be comparable between SHAM and SVF groups.

Our results highlight the effectiveness of SVF and its high therapeutic potential to improve sensorimotor functions and to restore the segmental sensorimotor loop and the communication between supra- and sub-lesional spinal cord regions after traumatic contusion.

Exosomes are the smallest subset of extracellular signaling vesicles secreted by most cells with the ability to communicate with other tissues and cell types over long distances. Their use in regenerative medicine has gained tremendous momentum recently due to their ability to be utilized as therapeutic options for a wide array of diseases/conditions. Over 5000 publications are currently being published yearly on this topic, and this number is only expected to dramatically increase as novel therapeutic strategies continue to be developed. Today exosomes have been applied in numerous contexts including neurodegenerative disorders (Alzheimer's disease, central nervous system, depression, multiple sclerosis, Parkinson's disease, post-traumatic stress disorders, traumatic brain injury, peripheral nerve injury), damaged organs (heart, kidney, liver, stroke, myocardial infarctions, myocardial infarctions, ovaries), degenerative processes (atherosclerosis, diabetes, hematology disorders, musculoskeletal degeneration, osteoradionecrosis, respiratory disease), infectious diseases (COVID-19, hepatitis), regenerative procedures (antiaging, bone regeneration, cartilage/joint regeneration, osteoarthritis, cutaneous wounds, dental regeneration, dermatology/skin regeneration, erectile dysfunction, hair regrowth, intervertebral disc repair, spinal cord injury, vascular regeneration), and cancer therapy (breast, colorectal, gastric cancer and osteosarcomas), immune function (allergy, autoimmune disorders, immune regulation, inflammatory diseases, lupus, rheumatoid arthritis). This scoping review is a first of its kind aimed at summarizing the extensive regenerative potential of exosomes over a broad range of diseases and disorders.

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.

Spinal cord injury (SCI) due to lack of restoration of damaged neuronal cells is associated with sensorimotor impairment. This study was focused on using the human placental mesenchymal stem cells- exosome (HPMSCs- Exosomes) in an animal model of severe SCI under myelogram procedure.

Intrathecal injection of exosomes was performed in the acute phase of SCI in female rats. The improved functional recovery of the animals was followed for 6 weeks in control (saline, n = 6) and HPMSCs- EXO (HPMSCs-Exosomes, n = 6) groups. Pathological changes and glial scar size were evaluated. The Immunohistochemistry (IHC) of GFAP and NF200 factors as well as the apoptosis assay was investigated in the tissue samples from the injury site. The results demonstrated that HPMSCs-exosomes can improve motor function by attenuating apoptosis of neurons at the injury site, decreasing GFAP expression and increasing NF200 in the HPMSCs-EXO group. Also, HPMSCs-exosomes by preventing the formation of cavities causes preservation of tissue in SCI rats.

These findings demonstrate the effectiveness of HPMSC-Exosomes as a therapeutic method to improve functional recovery, reduce pathological changes associated with injury, and prevent chronicity after SCI. The neuroprotective and anti-apoptotic potential of HPMSCs- Exosomes may be a promising therapeutic approach for SCI. Another result was the importance of intrathecal injection of exosomes in the acute phase, which accelerated the healing process. Furthermore, the myelogram can be a feasible and suitable method to confirm the accuracy of intrathecal injection and examine the subarachnoid space in the laboratory animals.

After spinal cord injury (SCI), the accumulation of myelin debris at the lesion exacerbates cell death and hinders axonal regeneration. Transplanted bone marrow mesenchymal stem cells (BMSCs) have been proven to be beneficial for SCI repair, but they are susceptible to apoptosis. It remains unclear whether this apoptotic process is influenced by myelin debris. Here, we constructed rat BMSCs overexpressing human B-cell lymphoma 2 (hBcl2) alone (hBcl2 group), BMSCs overexpressing hBcl2 with an endoplasmic reticulum-anchored segment (hBcl2-cb) (cb group), and a negative control group (NC group) for transplantation in this study. Immunocytochemistry staining validated the successful expression of hBcl2 in BMSCs within the hBcl2 group and cb group. All BMSCs from each group exhibited the ability to phagocytize myelin debris. Nevertheless, only BMSCs derived from the hBcl2 group exhibited heightened resistance to apoptosis and maintained prolonged viability for up to 5 days when exposed to myelin debris. Notably, overexpression of hBcl2 protein, rather than its endoplasmic reticulum-anchored counterpart, significantly enhanced the resistance of BMSCs against myelin debris-induced apoptosis. This process appeared to be associated with the efficient degradation of myelin debris through the Lamp1+ lysosomal pathway in the hBcl2 group. In vivo, the hBcl2 group exhibited significantly higher numbers of surviving cells and fewer apoptotic BMSCs compared to the cb and NC groups following transplantation. Furthermore, the hBcl2 group displayed reduced GFAP+ glial scarring and greater preservation of NF200+ axons in the lesions of SCI rats. Our results suggest that myelin debris triggers apoptosis in transplanted BMSCs, potentially elucidating the low survival rate of these cells after SCI. Consequently, the survival rate of transplanted BMSCs is improved by hBcl2 overexpression, leading to enhanced preservation of axons within the injured spinal cord.