Various detailed characteristics of a new enhanced neurotrophic factor secreting rat derived bone marrow mesenchymal stem cells and its preliminary application in rat models of ischemic stroke.

Because MSC-NTF has a higher ability to secrete neurotrophic factors, it may have a greater potential than ordinary MSC in clinical applications. At present, research on MSC-NTF mainly focuses on clinical aspects, but its basic research is relatively few. In particular, the research on the comprehensive and detailed characteristics of MSC-NTF is missing. And its in vivo research in animals is also rare. Since the transplantation of human-derived MSC-NTF into rats is cross-species, its survival in the rat and the therapeutic effect may be seriously affected due to severe immune rejection. This will inevitably affect the research on the basic characteristics and the therapeutic mechanisms of MSC-NTF in vivo. Therefore, we chose the rat-derived MSCs to be induced as the MSC-NTF which had a stronger neurotrophic factor secretion function. This will also be helpful to perform the research of the basic therapeutic mechanisms of MSC-NTF in vivo. In addition, we have established some important characteristics that can be used to distinguish between MSC-NTF and MSCs: different multi-factor secretion ability and secretion characteristics, immunogenicity, three-line differentiation ability, stemness, etc. In addition to paying attention to their safety differences, this study also explored the differences in their in vivo survivability. Finally, we applied this newly induced rat-derived MSC-NTF in a rat model of ischemic stroke, and obtained beneficial therapeutic effects.

The clinical relevance of epithelial-mesenchymal transition and its correlations with tumorigenic immune infiltrates in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a cancer with extremely high mortality. Epithelial-mesenchymal transition (EMT) may play an important role in the occurrence, invasion and prognosis of HCC; however, its relationship with immunity in HCC has not yet been studied. Therefore, we investigated the diagnostic and prognostic values of EMT and explored its potential connections with tumorigenic immune infiltrates in HCC. We first proposed a quantitative metric of EMT activity, the EMT score. After applying this metric to 20 datasets from the Integrative Molecular Database of Hepatocellular Carcinoma, the Cancer Genome Atlas, and the Gene Expression Omnibus, we explored the ability of the EMT score to stratify across sample types. We then applied the EMT score for survival analysis and to differentiate patients with/without vascular invasion to test its prognostic value. We also collected and calculated data on the abundance of immune cells and immune cell markers in HCC and investigated their correlations with EMT scores. Finally, we synthesized and analyzed 20 datasets and constructed an EMT-gene-immune linkage network. The results showed higher EMT scores in HCC samples than in cirrhotic and normal livers. The cases with higher EMT scores also showed poorer performance in terms of prognostic factors such as vascular invasion and overall survival time. Our research demonstrated a broad correlation between EMT and the tumor immune microenvironment, and we uncovered multiple potential linkers associated with both EMT and immunity. Studying EMT has clinical relevance and high diagnostic and prognostic value for HCC.

Comparative analysis of curative effect of bone marrow mesenchymal stem cell and bone marrow mononuclear cell transplantation for spastic cerebral palsy.

BACKGROUND: Bone marrow mesenchymal stem cells (BMMSCs) and bone marrow mononuclear cells (BMMNCs) are both used to treat spastic cerebral palsy. However, the differences in therapeutic effect remain unknown. METHODS: A total of 105 patients with spastic cerebral palsy were enrolled and randomly assigned to three groups: the BMMSC group, the BMMNC group and the control group. Patients in both transplantation groups received four intrathecal cell injections. Patients in the control group received Bobath therapy. The gross motor function measure (GMFM) and the fine motor function measure (FMFM) were used to evaluate the therapeutic efficacy before transplantation and 3, 6, and 12 months after transplantation. RESULTS: Three months after cell transplantation, scores in the A dimension of GMFM and the A and C dimensions of FMFM scores in the BMMSC group are all higher than those of the BMMNC and the control groups (P < 0.05). Six months after cell transplantation, scores in the A, B dimensions of GMFM and the A, B, C, D, and E dimensions of FMFM scores in the BMMSC group are higher than those of the BMMNC and the control groups (P < 0.05). Twelve months after cell transplantation, scores in the A, B, and C dimensions of GMFM and the A, B, C, D, and E dimensions of FMFM scores in the BMMSC group are all higher than those of the BMMNC and the control groups (P < 0.05). No obvious adverse effects were investigated during follow-up. CONCLUSIONS: BMMSC transplantation for the treatment of cerebral palsy is safe and feasible, and can improve gross motor and fine motor function significantly. In addition, compared with BMMNC, the motor function of children improved significantly in terms of gross motor and fine motor functions.

Effect of umbilical cord mesenchymal stromal cells on motor functions of identical twins with cerebral palsy: pilot study on the correlation of efficacy and hereditary factors.

BACKGROUND AIMS: The objective of this study was to compare the impact of umbilical cord-derived mesenchymal stromal cell (UCMSC) transplantation on the motor functions of identical twins with cerebral palsy (CP) and to analyze the correlation between the efficacy and hereditary factors. METHODS: Eight pairs (16 individuals) of identical twins with CP were recruited and received allogenic UCMSC transplantation by means of subarachnoid injection. The gross motor function measure (GMFM) and the fine motor function measure (FMFM) were performed before and 1 and 6 months after the treatment to analyze the results of individuals before and after the therapy, between two individuals of an identical twin and among twin pairs. Repeated-measured data variance was used to analyze the GMFM and FMFM scores of patients before and 1 and 6 months after the therapy. RESULTS: Eight pairs (16 individuals) of children with CP had significant improvement in the GMFM at the end of the 1st and 6th months after the therapy compared with that before the therapy, whereas the amelioration of the FMFM was not statistically significant. The improvements in motor functions between two individuals of an identical twin but not among twin pairs were correlated. CONCLUSIONS: UCMSC transplantation significantly improves GMFM in children with CP; motor function improvements in the GMFM between two individuals of an identical twin were closely correlated, but improvements among twin pairs were not correlated. We hypothesize that hereditary factors contribute to the mechanisms of UCMSC transplantation in motor function improvement in children with CP.

Clinical observation of umbilical cord mesenchymal stem cell transplantation in treatment for sequelae of thoracolumbar spinal cord injury.

BACKGROUND: Umbilical cord mesenchymal stem cells (UCMSCs) have a considerable advantage and potential in treating for central nervous system diseases and have become a novel alternative treatment for spinal cord injury. This study aims to compare the neurological function outcome of stem cell transplantation, rehabilitation therapy, and self-healing for sequelae of spinal cord injury. METHODS: Thirty-four cases of thoracolumbar spinal cord injury were randomly divided into three groups: the stem cell transplantation group was given CT-guided UCMSC transplantation twice; the rehabilitation group received rehabilitation therapy; and the blank control group did not receive any specific treatment. AIS grading, ASIA scoring, the manual muscle strength and muscle tension scale, and the Barthel index were used to evaluate the clinical outcome. Urodynamic examination was also performed for patients in the UCMSC group and the rehabilitation therapy group. RESULTS: Seven of the ten patients in the UCMSC group had significant and stable improvement in movement, self-care ability, and muscular tension; five of the forteen patients (36%) in the rehabilitation group also had certain improvement in these aspects. Urodynamic examination demonstrated that patients in the UCMSC group exhibited an increase in maximum urinary flow rate and maximum bladder capacity, as well as a decrease in residue urine volume and maximum detrusor pressure. The rehabilitation group exhibited decreased maximum bladder capacity, but no perceptible change in maximum urinary flow rate, residue urine volume or maximum detrusor pressure. CONCLUSIONS: UCMSC transplantation can effectively improve neurological functional recovery after spinal cord injury, and its efficacy is superior to that of rehabilitation therapy and self-healing. TRIAL REGISTRATION: The present clinical study was registered at chictr.org (registration number: NCT01393977).

Preclinical safety evaluation of human mesenchymal stem cell transplantation in cerebrum of nonhuman primates.

The efficacy of stem cell transplantation for promoting recovery of patients with neurological diseases, such as stroke, has been reported in several studies. However, the safety of the intracerebral transplantation of human mesenchymal stem cells (hMSCs) remains unclear. The aim of the study was to evaluate the safety of hMSCs transplanted in cerebrum of Macaca fascicularis and to provide evidence for clinical application. A total of 24 M fascicularis were assigned to 3 groups randomly: low dose (3.0 × 10(5) cells/kg), high dose (2.5 × 10(6) cells/kg), and the control (normal saline [NS]). Human mesenchymal stem cells or NS were injected into each monkey for 2 times, with an interval of 3 weeks. The injection point was located outside of the right putamen, according to a stereotactic map and preoperative magnetic resonance imaging of the monkeys. Animal health, behavior, biophysical and biochemical parameters, and brain neurological function were routinely monitored over a 6-month period posttransplantation, and the histopathologic examinations were also performed. The results showed that local pathologic damage including local tissue necrosis and inflammation was induced after the injection. The damage of low-dose and high-dose groups was greater than that of the control group, yet over time, the damage could be repaired gradually. No major hMSCs-associated changes were induced from other indicators, and the transplantation of hMSCs in monkeys did not affect total immunoglobulin (Ig) M, total IgG, CD3, CD4, or CD8 values. We therefore conclude that transplantation of hMSCs to the cerebrum represents a safe alternative for clinical application of neurological disorders.

High expression of SIGLEC7 may promote M2-type macrophage polarization leading to adverse prognosis in glioma patients.

Introduction: Gliomas are the most common primary intracranial tumors, known for their high invasiveness and destructiveness. Sialic acid-binding immunoglobulin-like lectin 7 (SIGLEC7) is present in various immune cells, especially macrophages, and significantly affects immune homeostasis and cancer cell response. However, research on the role and prognostic impact of SIGLEC7 in glioma patients is currently limited. Methods: We utilized transcriptomic data from 702 glioma patients in The Cancer Genome Atlas (TCGA) and 693 glioma patients in the Chinese Glioma Genome Atlas (CGGA), along with clinical samples we collected, to comprehensively investigate the impact of SIGLEC7 on glioma expression patterns, biological functions, and prognostic value. We focused on its role in glioma-related immune responses and immune cell infiltration and analyzed its expression at the single-cell level. Finally, we validated the role of SIGLEC7 in gliomas through tissue and cell experiments. Results: SIGLEC7 expression was significantly increased in glioma patients with malignant characteristics. Survival analysis indicated that glioma patients with high SIGLEC7 expression had significantly lower survival rates. Gene function analysis revealed that SIGLEC7 is primarily involved in immune and inflammatory responses and is strongly negatively correlated with tumor-associated immune regulation. Additionally, the expression of most immune checkpoints was positively correlated with SIGLEC7, and immune cell infiltration analysis clearly demonstrated a significant positive correlation between SIGLEC7 expression and M2 macrophage infiltration levels. Single-cell analysis, along with tissue and cell experiments, confirmed that SIGLEC7 enhances macrophage polarization towards the M2 phenotype, thereby promoting glioma invasiveness through the immunosuppressive effects of M2 macrophages. Cox regression analysis and the establishment of survival prediction models indicated that high SIGLEC7 expression is an unfavorable prognostic factor for glioma patients. Discussion: High SIGLEC7 expression predicts poor prognosis in glioma patients and is closely associated with M2 macrophages in the tumor environment. In the future, SIGLEC7 may become a promising target for glioma immunotherapy.

Identification of crosstalk genes and immune characteristics between Alzheimer's disease and atherosclerosis.

Background: Advancements in modern medicine have extended human lifespan, but they have also led to an increase in age-related diseases such as Alzheimer's disease (AD) and atherosclerosis (AS). Growing research evidence indicates a close connection between these two conditions. Methods: We downloaded four gene expression datasets related to AD and AS from the Gene Expression Omnibus (GEO) database (GSE33000, GSE100927, GSE44770, and GSE43292) and performed differential gene expression (DEGs) analysis using the R package "limma". Through Weighted gene correlation network analysis (WGCNA), we selected the gene modules most relevant to the diseases and intersected them with the DEGs to identify crosstalk genes (CGs) between AD and AS. Subsequently, we conducted functional enrichment analysis of the CGs using DAVID. To screen for potential diagnostic genes, we applied the least absolute shrinkage and selection operator (LASSO) regression and constructed a logistic regression model for disease prediction. We established a protein-protein interaction (PPI) network using STRING (https://cn.string-db.org/) and Cytoscape and analyzed immune cell infiltration using the CIBERSORT algorithm. Additionally, NetworkAnalyst (http://www.networkanalyst.ca) was utilized for gene regulation and interaction analysis, and consensus clustering was employed to determine disease subtypes. All statistical analyses and visualizations were performed using various R packages, with a significance level set at p<0.05. Results: Through intersection analysis of disease-associated gene modules identified by DEGs and WGCNA, we identified a total of 31 CGs co-existing between AD and AS, with their biological functions primarily associated with immune pathways. LASSO analysis helped us identify three genes (C1QA, MT1M, and RAMP1) as optimal diagnostic CGs for AD and AS. Based on this, we constructed predictive models for both diseases, whose accuracy was validated by external databases. By establishing a PPI network and employing four topological algorithms, we identified four hub genes (C1QB, CSF1R, TYROBP, and FCER1G) within the CGs, closely related to immune cell infiltration. NetworkAnalyst further revealed the regulatory networks of these hub genes. Finally, defining C1 and C2 subtypes for AD and AS respectively based on the expression profiles of CGs, we found the C2 subtype exhibited immune overactivation. Conclusion: This study utilized gene expression matrices and various algorithms to explore the potential links between AD and AS. The identification of CGs revealed interactions between these two diseases, with immune and inflammatory imbalances playing crucial roles in their onset and progression. We hope these findings will provide valuable insights for future research on AD and AS.

Comparative analysis of curative effect of CT-guided stem cell transplantation and open surgical transplantation for sequelae of spinal cord injury.

BACKGROUND: This study compared the clinical efficacies, advantages and disadvantages of two transplantation approaches for treating spinal cord injury: open surgical exploration combined with local stem cell transplantation (referred to as open surgical transplantation) and local stem cell transplantation by CT-guided puncture (referred to as CT-guided transplantation). METHODS: The patients were divided into the following three groups to perform a retrospective controlled study: Group A included nine patients who underwent open surgical transplantation, Group B included nine patients who underwent CT-guided transplantation, and Group C included nine patients who did not receive stem cell transplantation. The Abbreviated Injury Scale (AIS), the American Spinal Injury Association (ASIA) score and the motor evoked potentials (MEP) examination were utilized to compare the differences in the clinical efficacies. The advantages and disadvantages of the two transplantation approaches were also compared, including the surgical risks, the possibility of repeating the operation, the interval between surgery and rehabilitation exercises and the scope of conditions suitable for the operation. RESULTS: Whether evaluated by the AIS grading scale, the ASIA score or the MEP results, there were significant differences in the clinical efficacy among the three patient groups. Group B exhibited the best clinical outcome, followed by Group A, and Group C fared the worst. The CT-guided transplantation had the advantages of lower surgical risk, the potential to repeat the operations within a short time-frame and a short interval between surgery and rehabilitation exercise compared with the open surgical transplantation. The conditions that are suitable for CT-guided transplantation versus the conditions suitable for open surgical transplantation are not identical. The application scopes for the two approaches had their respective strengths. CONCLUSIONS: CT-guided stem cell transplantation was confirmed as a safe and effective approach to treat sequelae of spinal cord injury with the advantages of simpler operation, minimal invasion, less adverse reaction and quicker recovery. CLINICAL TRIALS REGISTRATION NUMBER: ChiCTR-TNRC-12002477.

Effects of bone marrow mesenchymal stromal cells on gross motor function measure scores of children with cerebral palsy: a preliminary clinical study.

BACKGROUND AIMS: Pre-clinical evidence indicates that autologous bone marrow-derived mesenchymal stromal cell (BM-MSC) transplantation improves motor function in patients with central nervous system disorders. METHODS: After providing informed consent, 52 patients with cerebral palsy (CP) who met the study criteria received BM-MSC transplantation. Gross motor function was assessed using the Gross Motor Function Measure (GMFM)-88 and GMFM-66 scales at baseline (before transplantation) and at 1 month, 6 months and 18 months post-transplantation. The participants completed the trial without visible side effects. The GMFM-66 percentile (motor growth curves) was used as the control index of motor function to exclude the interference of improvement with age. RESULTS: The score domains A, B, C and D and the total GMFM-88 and GMFM-66 scores in participants increased at 1 month, 6 months and 18 months post-transplantation compared with the baseline value (P < 0.01). The scores of domain E also increased at 6 months and 18 months post-transplantation, although they were not significantly increased at 1 month post-transplantation. There were significant increases in the GMFM-66 score and the GMFM-66 percentile corresponding to patient age and Gross Motor Function Classification System level after cell transplantation. CONCLUSIONS: Autologous BM-MSC transplantation appears to be a feasible, safe and effective therapy for patients with CP. The treatment improved the development of children with CP with regard to motor function.

Identification of immune-related biomarkers co-occurring in acute ischemic stroke and acute myocardial infarction.

Background: Acute ischemic stroke (AIS) and acute myocardial infarction (AMI) share several features on multiple levels. These two events may occur in conjunction or in rapid succession, and the occurrence of one event may increase the risk of the other. Owing to their similar pathophysiologies, we aimed to identify immune-related biomarkers common to AIS and AMI as potential therapeutic targets. Methods: We identified differentially expressed genes (DEGs) between the AIS and control groups, as well as AMI and control groups using microarray data (GSE16561 and GSE123342). A weighted gene co-expression network analysis (WGCNA) approach was used to identify hub genes associated with AIS and/or AMI progression. The intersection of the four gene sets identified key genes, which were subjected to functional enrichment and protein-protein interaction (PPI) network analyses. We confirmed the expression levels of hub genes using two sets of gene expression profiles (GSE58294 and GSE66360), and the ability of the genes to distinguish patients with AIS and/or AMI from control patients was assessed by calculating the receiver operating characteristic values. Finally, the investigation of transcription factor (TF)-, miRNA-, and drug-gene interactions led to the discovery of therapeutic candidates. Results: We identified 477 and 440 DEGs between the AIS and control groups and between the AMI and control groups, respectively. Using WGCNA, 2,776 and 2,811 genes in the key modules were identified for AIS and AMI, respectively. Sixty key genes were obtained from the intersection of the four gene sets, which were used to identify the 10 hub genes with the highest connection scores through PPI network analysis. Functional enrichment analysis revealed that the key genes were primarily involved in immunity-related processes. Finally, the upregulation of five hub genes was confirmed using two other datasets, and immune infiltration analysis revealed their correlation with certain immune cells. Regulatory network analyses indicated that GATA2 and hsa-mir-27a-3p might be important regulators of these genes. Conclusion: Using comprehensive bioinformatics analyses, we identified five immune-related biomarkers that significantly contributed to the pathophysiological mechanisms of both AIS and AMI. These biomarkers can be used to monitor and prevent AIS after AMI, or vice versa.

Clinical and biological significance of RNA N6-methyladenosine regulators in Alzheimer disease.

RNA N6-methyladenosine (m6A) regulators are essential for a variety of biological functions, such as early development, viral infections, and cancer. However, their roles in Alzheimer disease (AD) are still not very clear. Here, 16 significant m6A regulators were identified using difference analysis between AD patients and non-demented controls based on the GSE132903 dataset from the Gene Expression Omnibus database. Using these 16 m6A regulators, a nomogram model was established to predict the prevalence of AD. We found that patients could obtain a good clinical benefit based on this model. In addition, we revealed 2 distinct m6A patterns and 2 distinct m6A gene patterns in AD and demonstrated their prognostic and risk assessment significance. This present work comprehensively evaluated the functions of m6A regulators in the diagnosis and subtype classification of AD. These results suggested they have potential prognostic and risk assessment significance in AD.

Treatment of one case of cerebral palsy combined with posterior visual pathway injury using autologous bone marrow mesenchymal stem cells.

BACKGROUND: Cerebral palsy is currently one of the major diseases that cause severe paralysis of the nervous system in children; approximately 9-30% of cerebral palsy patients are also visually impaired, for which no effective treatment is available. Bone marrow mesenchymal stem cells (BMSCs) have very strong self-renewal, proliferation, and pluripotent differentiation potentials. Therefore, autologous BMSC transplantation has become a novel method for treating cerebral palsy. METHODS: An 11-year-old boy had a clear history of dystocia and asphyxia after birth; at the age of 6 months, the family members observed that his gaze roamed and noted that he displayed a lack of attention. A brain MRI examination at the age of 7 years showed that the child had cerebral palsy with visual impairment (i.e., posterior visual pathway injury). The patient was hospitalized for 20 days and was given four infusions of intravenous autologous BMSCs. Before transplantation and 1, 6, and 12 months after transplantation, a visual evoked potential test, an electrocardiogram, routine blood tests, and liver and kidney function tests were performed. RESULTS: The patient did not have any adverse reactions during hospitalization or postoperative follow-up. After discharge, the patient could walk more smoothly than he could before transplantation; furthermore, his vision significantly improved 6 months after transplantation, which was also supported by the electrophysiological examinations. CONCLUSIONS: The clinical application of BMSCs is effective for improving vision in a patient with cerebral palsy combined with visual impairment.

Preconditioning with Trehalose Protects the Bone Marrow-Derived Mesenchymal Stem Cells Under Oxidative Stress and Enhances the Stem Cell-Based Therapy for Cerebral Ischemic Stroke.

Bone marrow-derived mesenchymal stem cell (BMSC) transplantation has emerged as a potential treatment for ischemic stroke. Preconditioning with pharmacological agents before cell transplantation has been shown to increase the efficiency of cell therapy. In this study, trehalose (Tre), an autophagy inducer, was used as a pharmacological agent to treat BMSCs, and the neuroprotective effect of BMSCs preconditioned with Tre on cerebral ischemia was assessed. BMSCs were treated in vitro with different concentrations of Tre. Immunofluorescence staining of LC3B was performed to detect autophagy, and Western blotting for LC3, Beclin1, p-AMPK, and p-mTOR was performed. Flow cytometry and Western blotting analysis were performed to measure cell apoptosis in the presence of hydrogen peroxide (H2O2). Enzyme-linked immunosorbent assay was used to test the secretion levels of neurotrophic factors. An in vivo ischemia/reperfusion model was generated by middle cerebral artery occlusion in male Sprague Dawley rats, and Tre-preconditioned BMSCs were administered intralesionally 24 hours after ischemic injury. Histopathological examination and neurological function studies were conducted. In vitro, Tre promotes autophagy of BMSCs through the activation of the AMPK signal pathway. Tre protected BMSCs from H2O2-induced cell viability reduction and apoptosis. Moreover, Tre pretreatment increased the secretion of brain-derived neurotrophic factor, vascular endothelial growth factor, and hepatocyte growth factor. In vivo, preconditioning with Tre could further enhance the survival of BMSCs, reduce infarct size, alleviate cell apoptosis, abate vessel decrease, and ultimately improve functional recovery. Our study indicates that Tre can enhance the survival of BMSCs under oxidative stress and enhance BMSC-based treatment of ischemia/reperfusion injury.

The significance of glycolysis index and its correlations with immune infiltrates in Alzheimer's disease.

Alzheimer's disease (AD) is a common neurodegenerative disorder without an effective treatment, and results in an increasingly serious health problem. However, its pathogenesis is complex and poorly understood. Nonetheless, the exact role of dysfunctional glucose metabolism in AD pathogenesis remains unclear. We screened 28 core glycolysis-related genes and introduced a novel metric, the glycolysis index, to estimate the activation of glycolysis. The glycolysis index was significantly lower in the AD group in four different brain regions (frontal cortex, FC; temporal cortex, TC; hippocampus, HP; and entorhinal cortex, EC) than that in the control group. Combined with differential expression and over-representation analyses, we determined the clinical and pathological relevance of glycolysis in AD. Subsequently, we investigated the role of glycolysis in the AD brain microenvironment. We developed a glycolysis-brain cell marker connection network, which revealed a close relationship between glycolysis and seven brain cell types, most of which presented abundant variants in AD. Using immunohistochemistry, we detected greater infiltrated microglia and higher expression of glycolysis-related microglia markers in the APP/PS1 AD model than that in the control group, consistent with our bioinformatic analysis results. Furthermore, the excellent predictive value of the glycolysis index has been verified in different populations. Overall, our present findings revealed the clinical and biological significance of glycolysis and the brain microenvironment in AD.

Single-cell Transcriptomic Analysis Reveals the Cellular Heterogeneity of Mesenchymal Stem Cells.

Ex vivo-expanded mesenchymal stem cells (MSCs) have been demonstrated to be a heterogeneous mixture of cells exhibiting varying proliferative, multipotential, and immunomodulatory capacities. However, the exact characteristics of MSCs remain largely unknown. By single-cell RNA sequencing of 61,296 MSCs derived from bone marrow and Wharton's jelly, we revealed five distinct subpopulations. The developmental trajectory of these five MSC subpopulations was mapped, revealing a differentiation path from stem-like active proliferative cells (APCs) to multipotent progenitor cells, followed by branching into two paths: 1) unipotent preadipocytes or 2) bipotent prechondro-osteoblasts that were subsequently differentiated into unipotent prechondrocytes. The stem-like APCs, expressing the perivascular mesodermal progenitor markers CSPG4/MCAM/NES, uniquely exhibited strong proliferation and stemness signatures. Remarkably, the prechondrocyte subpopulation specifically expressed immunomodulatory genes and was able to suppress activated CD3+ T cell proliferation in vitro, supporting the role of this population in immunoregulation. In summary, our analysis mapped the heterogeneous subpopulations of MSCs and identified two subpopulations with potential functions in self-renewal and immunoregulation. Our findings advance the definition of MSCs by identifying the specific functions of their heterogeneous cellular composition, allowing for more specific and effective MSC application through the purification of their functional subpopulations.

Transplantation of Flk-1+ human bone marrow-derived mesenchymal stem cells promotes angiogenesis and neurogenesis after cerebral ischemia in rats.

Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) is a potential therapy for cerebral ischemia. Although BMSCs-induced angiogenesis is considered important for neurological functional recovery, the neurorestorative mechanisms are not fully understood. We examined whether BMSCs-induced angiogenesis enhances cerebral tissue perfusion and creates a suitable microenvironment within the ischemic brain, which in turn accelerates endogenous neurogenesis and leads to improved functional recovery. Adult female rats subjected to 2 h middle cerebral artery occlusion (MCAO) were transplanted with a subpopulation of human BMSCs from male donors (Flk-1+ hBMSCs) or saline into the ipsilateral brain parenchymal at 3 days after MCAO. Flk-1+ hBMSCs-treated rats exhibited significant behavioral recovery, beginning at 2 weeks after cerebral ischemia compared with controls. Moreover, rats treated with Flk-1+ hBMSCs showed increased glucose metabolic activity and reduced infarct volume. Flk-1+ hBMSCs treatment significantly increased the expression of vascular endothelial growth factor and brain-derived neurotrophic factor, promoted angiogenesis, and facilitated cerebral blood flow in the ischemic boundary zone. Further, Flk-1+ hBMSCs treatment enhanced proliferation of neural stem/progenitor cells (NSPCs) in the subventricular zone and subgranular zone of the hippocampus. Finally, more NSPCs migrated toward the ischemic lesion and differentiated to mature neurons or glial cells with less apoptosis in Flk-1+ hBMSCs-treated rats. These data indicate that angiogenesis induced by Flk-1+ hBMSCs promotes endogenous neurogenesis, which may cause functional recovery after cerebral ischemia.

Modulation of the major histocompatibility complex by neural stem cell-derived neurotrophic factors used for regenerative therapy in a rat model of stroke.

BACKGROUND: The relationship between functional improvements in ischemic rats given a neural stem cell (NSC) transplant and the modulation of the class I major histocompatibility complex (MHC) mediated by NSC-derived neurotrophins was investigated. METHODS: The levels of gene expression of nerve growth factor (NGF), brain-derived neurotropic factor (BDNF) and neurotrophin-3 (NT-3) were assayed from cultures of cortical NSC from Sprague-Dawley rat E16 embryos. The levels of translated NGF in spent culture media from NSC cultures and the cerebral spinal fluid (CSF) of rats with and without NGF injection or NSC transplant were also measured. RESULTS: We found a significant increase of NGF, BDNF and NT-3 transcripts and NGF proteins in both the NSC cultures and the CSF of the rats. The immunochemical staining for MHC in brain sections and the enzyme-linked immunosorbent assay of CSF were carried out in sham-operated rats and rats with surgically induced focal cerebral ischemia. These groups were further divided into animals that did and did not receive NGF administration or NSC transplant into the cisterna magna. Our results show an up-regulation of class I MHC in the ischemic rats with NGF and NSC administration. The extent of caspase-III immunoreactivity was comparable among three arms in the ischemic rats. CONCLUSION: Readouts of somatosensory evoked potential and the trap channel test illustrated improvements in the neurological function of ischemic rats treated with NGF administration and NSC transplant.

A novel workflow for cancer blood biomarker identification.

BACKGROUND: Over the last few years, great progress has been made in the development of key technologies to detect peripheral blood-based, tumor-specific biomarkers, such as circulating tumor cells (CTCs) and circulating cell free tumor DNA (ctDNA). Despite the considerable advances and their multiple clinical values, liquid biopsies are challenged by the very low concentrations of CTCs and ctDNA in blood samples. Additionally, blood biomarkers which were found using data-driven methods may only be effective in few datasets. METHODS: We firstly collected the genes which have expression correlations between blood and the other tissues/organs using Genotype-Tissue Expression (GTEx). Survival hazard genes and differential expression genes of each cancer type in The Cancer Genome Atlas (TCGA) were then selected by Cox regression model and Wilcoxon rank sum test, respectively. By combining the P values of two steps, several blood biomarkers can be inferred for each cancer type. After applying these potential blood biomarker sets to 13 datasets of blood samples from solid tumor patients using single sample gene set enrichment analyses (ssGSEA), we got an enrichment score (ES) for each sample. RESULTS: The inferred blood biomarker (BB infer) genes showed reliable predictive value in various malignancies. In all the blood samples that were analyzed, the ESs of positive BB Infer genes in cancer patients are higher than healthy people. Conversely, the ESs of negative BB Infer genes in cancer patients are lower than healthy people. Furthermore, lower ES of negative BB infer genes signify the dismal outcome of patients. CONCLUSIONS: We developed a novel solid tumor blood biomarker inference workflow for cancer screening and diagnosis. Moreover, we demonstrated the utility of this inference method in a series of blood sample datasets of solid tumor patients. These results suggested the potential value of this method in the screening, diagnosis and prognosis of cancers.

The Prognostic Value of EMT in Glioma and its Role in the Glioma Immune Microenvironment.

Diffuse glioma is the deadliest form of brain cancer, and the median survival of grade IV glioma (glioblastoma, GBM) is no more than 2 years even with maximal surgical resection followed by radiotherapy and chemotherapy, which are now the standard of care for GBM. Glioma shares common characteristics with most malignant tumours, such as invasiveness, rapid progression, resistance to various therapies and inevitable recurrence, while it also has its own unique features, such as high aggressiveness and immunotherapy resistance, which can be, respectively, attributed to epithelial-mesenchymal transition (EMT) and the immunosuppressive microenvironment. Here, we calculated the EMT score of glioma using The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA) and the Gene Expression Omnibus (GEO) datasets and validated its prognostic value. Then, we investigated its role in the glioma immune microenvironment, identified the enriched EMT-related immune genes and determined their specific biological functions in glioma. Furthermore, clinical relevance analysis showed the translational value of these EMT-related immune genes. In short, our findings reveal a critical link between EMT and the glioma immune microenvironment and offer important clues for further investigation of the underlying molecular mechanism.