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Purpose: Cognitive dysfunction caused by chronic cerebral hypoperfusion (CCH) is the leading cause of vascular dementia. Therefore, it is necessary to explore the mechanism that causes cerebral injury and find an effective therapy. Methods: Bone marrow mononuclear cells (BMMNCs) were extracted to detect the activity by CCK-8 kit and verify the transfection efficiency using reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR). A CCH rat model was established. Superparamagnetic iron oxide nanoparticles (BMPs)-PEI-Slit2/BMMNCs were injected into the tail vein and intervened with an external magnetic field. Hematoxylin and eosin staining was used to observe the pathological changes in brain tissue. The Slit/Robo pathway-related proteins Slit2 and Robo4 were detected by RT-qPCR and Western blotting. Results: The neurological score of the CCH group significantly increased compared with that of the sham group (P<0.05). The levels of brain injury markers S-100ß and NSE were significantly higher in the CCH group than in the sham group (P<0.05). Neuronal apoptosis in the frontal cortex and hippocampus of CCH rats significantly increased compared with that of the sham group (P<0.05). The expression levels of Slit2 and Robo4 mRNAs and proteins in brain tissue of CCH rats significantly increased (P<0.05). The neurological function scores of CCH rats treated with BMP-PEI-Slit2/BMMNC significantly increased after Robo4 siRNA administration (P<0.05). Conclusion: BMP combination with the CCH-related gene Slit2 can effectively improve the efficiency of BMMNC transplantation in treatment.
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Isquemia Encefálica , Disfunción Cognitiva , Modelos Animales de Enfermedad , Péptidos y Proteínas de Señalización Intercelular , Proteínas del Tejido Nervioso , Animales , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Ratas , Disfunción Cognitiva/terapia , Disfunción Cognitiva/etiología , Isquemia Encefálica/terapia , Isquemia Encefálica/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Humanos , Masculino , Nanopartículas de Magnetita/administración & dosificación , Nanopartículas de Magnetita/química , Nanopartículas Magnéticas de Óxido de Hierro/administración & dosificación , Células de la Médula Ósea , Apoptosis/genética , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Ratas Sprague-Dawley , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Terapia Genética/métodos , Proteínas RoundaboutRESUMEN
Ionizing radiation exposure can cause damage to diverse tissues and organs, with the hematopoietic system being the most sensitive. However, limited information is available regarding the radiosensitivity of various hematopoietic cell populations in the bone marrow due to the high heterogeneity of the hematopoietic system. In this study, we observed that granulocyte-macrophage progenitors, hematopoietic stem/progenitor cells, and B cells within the bone marrow showed the highest sensitivity, exhibiting a rapid decrease in cell numbers following irradiation. Nonetheless, neutrophils, natural killer (NK) cells, T cells, and dendritic cells demonstrated a certain degree of radioresistance, with neutrophils exhibiting the most pronounced resistance. By employing single-cell transcriptome sequencing, we investigated the early responsive genes in various cell types following irradiation, revealing that distinct gene expression profiles emerged between radiosensitive and radioresistant cells. In B cells, radiation exposure led to a specific upregulation of genes associated with mitochondrial respiratory chain complexes, suggesting a connection between these complexes and cell radiosensitivity. In neutrophils, radiation exposure resulted in fewer gene alterations, indicating their potential for distinct mechanisms in radiation resistance. Collectively, this study provides insights into the molecular mechanism for the heterogeneity of radiosensitivity among the various bone marrow hematopoietic cell populations.
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Radiación Ionizante , Análisis de la Célula Individual , Transcriptoma , Animales , Ratones , Análisis de la Célula Individual/métodos , Transcriptoma/efectos de la radiación , Células de la Médula Ósea/efectos de la radiación , Células de la Médula Ósea/metabolismo , Ratones Endogámicos C57BL , Tolerancia a Radiación/genética , Perfilación de la Expresión Génica , Células Madre Hematopoyéticas/efectos de la radiación , Células Madre Hematopoyéticas/metabolismo , Neutrófilos/efectos de la radiación , Neutrófilos/metabolismoRESUMEN
Cure rates for acute myeloid leukemia (AML) remain suboptimal; thus, new treatment strategies are needed for this deadly disease. Artemisia campestris leaves hold significant value in traditional medicine. Despite extensive research conducted on this plant globally, the specific anti-AML properties of the leaves have received limited investigation. This study aims to explore the potential anti-leukemic activities of the ethyl acetate extract derived from Artemisia campestris (EAEAC), using mononuclear cells from bone marrow of thirteen AML patients. To this end, cytotoxic effects were evaluated using the MTT assay, and the mechanisms of cell death were investigated through various methods, including propidium iodide staining, annexin V/propidium iodide double staining, mitochondrial depolarization, and caspase-3/7 activation assays. Results demonstrated that EAEAC induced cell apoptosis by increasing DNA fragmentation, causing mitochondrial depolarization, and activating caspases 3/7. On the other hand, we assessed EAEAC's effect on two leukemia stem cell subpopulations, with results suggesting a potential decrease in their frequencies (three/five patients).
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Apoptosis , Artemisia , Leucemia Mieloide Aguda , Extractos Vegetales , Humanos , Artemisia/química , Extractos Vegetales/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Apoptosis/efectos de los fármacos , Femenino , Adulto , Masculino , Persona de Mediana Edad , Caspasa 3/metabolismo , Antineoplásicos Fitogénicos/farmacología , Hojas de la Planta/químicaRESUMEN
BACKGROUND: There is no clear evidence on the comparative effectiveness of bone-marrow mononuclear cell (BMMNC) vs. mesenchymal stromal cell (MSC) stem cell therapy in patients with chronic heart failure (HF). METHODS: Using a systematic approach, eligible randomized controlled trials (RCTs) of stem cell therapy (BMMNCs or MSCs) in patients with HF were retrieved to perform a meta-analysis on clinical outcomes (major adverse cardiovascular events (MACE), hospitalization for HF, and mortality) and echocardiographic indices (including left ventricular ejection fraction (LVEF)) were performed using the random-effects model. A risk ratio (RR) or mean difference (MD) with corresponding 95% confidence interval (CI) were pooled based on the type of the outcome and subgroup analysis was performed to evaluate the potential differences between the types of cells. RESULTS: The analysis included a total of 36 RCTs (1549 HF patients receiving stem cells and 1252 patients in the control group). Transplantation of both types of cells in patients with HF resulted in a significant improvement in LVEF (BMMNCs: MD (95% CI) = 3.05 (1.11; 4.99) and MSCs: MD (95% CI) = 2.82 (1.19; 4.45), between-subgroup p = 0.86). Stem cell therapy did not lead to a significant change in the risk of MACE (MD (95% CI) = 0.83 (0.67; 1.06), BMMNCs: RR (95% CI) = 0.59 (0.31; 1.13) and MSCs: RR (95% CI) = 0.91 (0.70; 1.19), between-subgroup p = 0.12). There was a marginally decreased risk of all-cause death (MD (95% CI) = 0.82 (0.68; 0.99)) and rehospitalization (MD (95% CI) = 0.77 (0.61; 0.98)) with no difference among the cell types (p > 0.05). CONCLUSION: Both types of stem cells are effective in improving LVEF in patients with heart failure without any noticeable difference between the cells. Transplantation of the stem cells could not decrease the risk of major adverse cardiovascular events compared with controls. Future trials should primarily focus on the impact of stem cell transplantation on clinical outcomes of HF patients to verify or refute the findings of this study.
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Trasplante de Médula Ósea , Insuficiencia Cardíaca , Trasplante de Células Madre Mesenquimatosas , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Insuficiencia Cardíaca/terapia , Trasplante de Células Madre Mesenquimatosas/métodos , Trasplante de Médula Ósea/métodos , Volumen Sistólico , Resultado del Tratamiento , Células Madre Mesenquimatosas/citología , Función Ventricular IzquierdaRESUMEN
OBJECTIVES: This study investigated the therapeutic potential of fetal progenitor cells (FPCs) in the treatment of chronic non-healing wounds and ulcers associated with chronic limb ischemia (CLI). The research aimed to elucidate the mechanism of action of FPCs and evaluate their efficacy and safety in CLI patients. METHODS: The researchers isolated FPCs from aborted human fetal liver, brain, and skin tissues and thoroughly characterized them. The preclinical phase of the study involved assessing the effects of FPCs in a rat model of CLI. Subsequently, a randomized controlled clinical trial was conducted to compare the efficacy of FPCs with standard treatment and autologous bone marrow mononuclear cells in CLI patients. The clinical trial lasted 12 months, with a follow-up period of 24-36 months. The primary outcomes included wound healing, frequency of major and minor amputations, pain reduction, and the incidence of complications. Secondary outcomes involved changes in local hemodynamics and histological, ultrastructural, and immunohistochemical assessments of angiogenesis. RESULTS: In the animal model, FPC treatment significantly enhanced angiogenesis and accelerated healing of ischemic wounds compared to controls. The clinical trial in CLI patients demonstrated that the FPC therapy achieved substantially higher rates of complete wound closure, prevention of major amputation, pain reduction, and improvement in ankle-brachial index compared to control groups. Notably, the study reported no serious adverse events. CONCLUSIONS: FPC therapy exhibited remarkable efficacy in promoting the healing of ischemic wounds, preventing amputation, and improving symptoms and quality of life in patients with CLI. The proangiogenic and provasculogenic effects of FPCs may be attributed to their ability to secrete specific growth factors. These findings provide new insights into the development of cellular therapeutic angiogenesis as a promising approach for the treatment of peripheral arterial diseases.
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Pressure injuries, or pressure ulcers, are a common problem that may lead to infections and major complications, besides being a social and economic burden due to the costs of treatment and hospitalization. While surgery is sometimes necessary, this also has complications such as recurrence or wound dehiscence. Among the newer methods of pressure injury treatment, advanced therapies are an interesting option. This study examines the healing properties of bone marrow mononuclear cells (BM-MNCs) embedded in a plasma-based scaffold in a mouse model. Pressure ulcers were created on the backs of mice (2 per mouse) using magnets and assigned to a group of ulcers that were left untreated (Control, n = 15), treated with plasma scaffold (Plasma, n = 15), or treated with plasma scaffold containing BM-MNC (Plasma + BM-MNC, n = 15). Each group was examined at three time points (3, 7, and 14 days) after the onset of treatment. At each time point, animals were subjected to biometric assessment, bioluminescence imaging, and tomography. Once treatment had finished, skin biopsies were processed for histological and wound healing reverse transcription polymerase chain reaction (RT-PCR) array studies. While wound closure percentages were higher in the Plasma and Plasma + BM-MNC groups, differences were not significant, and thus descriptive data are provided. In all individuals, the presence of donor cells was revealed by immunohistochemistry on posttreatment onset Days 3, 7, and 14. In the Plasma + BM-MNC group, less inflammation was observed by positron emission tomography-computed tomography (PET/CT) imaging of the mice at 7 days, and a complete morphometabolic response was produced at 14 days, in accordance with histological results. A much more pronounced inflammatory process was observed in controls than in the other two groups, and this persisted until Day 14 after treatment onset. RT-PCR array gene expression patterns were also found to vary significantly, with the greatest difference noted between both treatments at 14 days when 11 genes were differentially expressed.
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Células de la Médula Ósea , Modelos Animales de Enfermedad , Úlcera por Presión , Cicatrización de Heridas , Animales , Úlcera por Presión/terapia , Úlcera por Presión/patología , Ratones , Células de la Médula Ósea/citología , Masculino , Andamios del Tejido/química , Ratones Endogámicos C57BL , Trasplante de Médula Ósea/métodos , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/trasplanteRESUMEN
BACKGROUND: Bone marrow mononuclear cells (BMMNCs) have great potential in bone regenerative therapy. The main method used today to obtain BMMNCs is Ficoll density gradient centrifugation. However, the centrifugal force for this isolation method is still suboptimal. OBJECTIVES: To determine the optimal centrifugal force in Ficoll density gradient centrifugation of bone marrow (BM) to achieve high stem/progenitor cell content BMMNCs for regenerative therapy. METHODS: BM was aspirated from nine minipigs and divided into three groups according to different centrifugal forces (200 g, 300 g and 400 g). Immediately after BMMNCs were obtained from each group by Ficoll density gradient centrifugation, residual red blood cell (RBC) level, nucleated cell counting, viability and flow cytometric analyses of apoptosis and reactive oxygen species (ROS) generation were measured. The phenotypic CD90 and colony formation analyses of BMMNCs of each group were performed as well. Bone marrow-derived mesenchymal stem cells (BMSCs) were harvested at passage 2, then morphology, cell phenotype, proliferation, adipogenic, chondrogenic and osteogenic lineage differentiation potential of BMSCs from each group were compared. RESULTS: The 300 g centrifugal force was able to isolate BMMNCs from BM with the same efficiency as 400 g and provided significantly higher yields of CD90+ BMSCs and fibroblastic colony-forming units of BMSC (CFU-f(BMSC)), which is more crucial for the regenerative efficacy of BMMNCs. Meanwhile, 200 g hosted the most RBC contamination and minimum CFU-f (BMSC) yield, which will be disadvantageous for BMMNC-based cell therapy. As for in vitro cultured BMSCs which were isolated from BMMNCs by different centrifugal forces, no significant differences were found on morphology, cell proliferation rate, phenotypic marker, adipogenic, chondrogenic and osteogenic differentiation potential. CONCLUSIONS: 300 g may be the optimal centrifugal force when using Ficoll density gradient centrifugation to isolate BMMNCs for bone regenerative therapy. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.
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Células de la Médula Ósea , Separación Celular , Centrifugación por Gradiente de Densidad , Animales , Porcinos , Centrifugación por Gradiente de Densidad/métodos , Células de la Médula Ósea/citología , Separación Celular/métodos , Porcinos Enanos , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/fisiología , Citometría de Flujo , Diferenciación Celular , Células Cultivadas , Leucocitos Mononucleares/citologíaRESUMEN
This report highlights the successful treatment of a Charcot-Marie-Tooth disease case using the Regentime stem cell procedure, suggesting its potential as a promising therapeutic approach for patients suffering from this challenging condition.
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BACKGROUND: Cell-based therapy represents a potential treatment for ischemic stroke (IS). Here, we performed a systematic review and meta-analysis to summarize the evidence provided by randomized controlled trials (RCTs) for the transplantation of bone marrow mononuclear cells (BMMNCs) in patients with IS in any phase after stroke. METHODS: We searched several databases for relevant articles up to the 10th of March 2023, including MEDLINE, EMBASE, the Cochrane Library, and ClinicalTrials.gov. Subgroup analyses were implemented to evaluate the dose and route of BMMNC administration. Statistical data were analyzed by Review Manager version 5.3 software. RESULTS: Six RCTs were included in this article, including 177 patients who were treated by the transplantation of BMMNCs and 166 patients who received medical treatment. The three-month National Institutes of Health Stroke Scale (NIHSS) score indicated a favorable outcome for the BMMNC transplantation group (standardized mean difference (SMD), - 0.34; 95% confidence interval (CI), - 0.57 to - 0.11; P = 0.004). There were no significant differences between the two groups at six months post-transplantation with regards to NIHSS score (SMD 0.00; 95% CI - 0.26 to 0.27; P = 0.97), modified Rankin Scale (risk ratio (RR) 1.10; 95% CI 0.75 to 1.63; P = 0.62), Barthel Index change (SMD 0.68; 95% CI - 0.59 to 1.95; P = 0.29), and infarct volume change (SMD - 0.08; 95% CI - 0.42 to 0.26; P = 0.64). In addition, there was no significant difference between the two groups in terms of safety outcome (RR 1.24; 95% CI 0.80 to 1.91; P = 0.33). CONCLUSION: Our meta-analysis demonstrated that the transplantation of BMMNCs was safe; however, the efficacy of this procedure requires further validation in larger RTCs.
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Trasplante de Médula Ósea , Accidente Cerebrovascular Isquémico , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Accidente Cerebrovascular Isquémico/terapia , Accidente Cerebrovascular Isquémico/cirugía , Trasplante de Médula Ósea/métodos , Recuperación de la Función/fisiologíaRESUMEN
Autologous bone marrow mononuclear cells (BMMNCs) infused after severe traumatic brain injury have shown promise for treating the injury. We evaluated their impact in children, particularly their hypothesized ability to preserve the blood-brain barrier and diminish neuroinflammation, leading to structural CNS preservation with improved outcomes. We performed a randomized, double-blind, placebo-sham-controlled Bayesian dose-escalation clinical trial at two children's hospitals in Houston, TX and Phoenix, AZ, USA (NCT01851083). Patients 5-17â years of age with severe traumatic brain injury (Glasgow Coma Scale score ≤ 8) were randomized to BMMNC or placebo (3:2). Bone marrow harvest, cell isolation and infusion were completed by 48 h post-injury. A Bayesian continuous reassessment method was used with cohorts of size 3 in the BMMNC group to choose the safest between two doses. Primary end points were quantitative brain volumes using MRI and microstructural integrity of the corpus callosum (diffusivity and oedema measurements) at 6â months and 12â months. Long-term functional outcomes and ventilator days, intracranial pressure monitoring days, intensive care unit days and therapeutic intensity measures were compared between groups. Forty-seven patients were randomized, with 37 completing 1-year follow-up (23 BMMNC, 14 placebo). BMMNC treatment was associated with an almost 3-day (23%) reduction in ventilator days, 1-day (16%) reduction in intracranial pressure monitoring days and 3-day (14%) reduction in intensive care unit (ICU) days. White matter volume at 1â year in the BMMNC group was significantly preserved compared to placebo [decrease of 19 891 versus 40 491, respectively; mean difference of -20 600, 95% confidence interval (CI): -35 868 to -5332; P = 0.01], and the number of corpus callosum streamlines was reduced more in placebo than BMMNC, supporting evidence of preserved corpus callosum connectivity in the treated groups (-431 streamlines placebo versus -37 streamlines BMMNC; mean difference of -394, 95% CI: -803 to 15; P = 0.055), but this did not reach statistical significance due to high variability. We conclude that autologous BMMNC infusion in children within 48 h after severe traumatic brain injury is safe and feasible. Our data show that BMMNC infusion led to: (i) shorter intensive care duration and decreased ICU intensity; (ii) white matter structural preservation; and (iii) enhanced corpus callosum connectivity and improved microstructural metrics.
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Trasplante de Médula Ósea , Lesiones Traumáticas del Encéfalo , Trasplante Autólogo , Humanos , Niño , Lesiones Traumáticas del Encéfalo/terapia , Masculino , Femenino , Adolescente , Método Doble Ciego , Preescolar , Trasplante de Médula Ósea/métodos , Trasplante Autólogo/métodos , Imagen por Resonancia Magnética , Resultado del Tratamiento , Leucocitos Mononucleares/trasplante , Teorema de BayesRESUMEN
BACKGROUND: Type 2 diabetes (T2D) is a progressive disease. Many drugs currently being used for the management of T2D have minimal effect on pancreatic beta cells regeneration. Cell-based therapies might provide potential benefits in this aspect. METHODS: A pilot study in five T2D patients with 12 months follow-up was performed to evaluate the effect of autologous bone marrow mononuclear stem cells (BM-MNCs) infusion into pancreatic arteries on the insulin requirement, beta-cell function, insulin resistance, and systemic inflammatory marker (CRP). RESULTS: The primary endpoint, a 50 % reduction of total insulin doses from baseline, was not achieved in this study. However, a trend of increasing fasting C-peptide (p = 0.07) and C-peptide 60' (p = 0.07) and 90' (p = 0.07) after a mixed-meal tolerance test was observed 12 months post-infusion compared to baseline levels. A similar result was observed for the homeostatic model assessment of beta cell function (HOMA1-B), an index for beta cell function. No improvement was observed for insulin resistance measured by homeostasis model assessment of insulin resistance (HOMA1-IR) and systemic inflammatory parameter. CONCLUSION: Intraarterial pancreatic autologous BM-MNCs infusion might potentially improve beta cell function in T2D patients, although further study is needed to confirm this finding.
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Trasplante de Médula Ósea , Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Células Secretoras de Insulina , Trasplante Autólogo , Humanos , Células Secretoras de Insulina/fisiología , Células Secretoras de Insulina/efectos de los fármacos , Diabetes Mellitus Tipo 2/terapia , Diabetes Mellitus Tipo 2/sangre , Masculino , Persona de Mediana Edad , Femenino , Trasplante de Médula Ósea/métodos , Proyectos Piloto , Biomarcadores , Insulina/administración & dosificación , Infusiones Intraarteriales , Páncreas , Adulto , Inflamación , Péptido C/sangre , Péptido C/análisis , Anciano , Leucocitos Mononucleares/trasplante , Leucocitos Mononucleares/metabolismoRESUMEN
Pediatric traumatic brain injury is a cause of major mortality, and resultant neurological sequelae areassociated with long-term morbidity. Increasing studies have revealed stem cell therapy to be a potential new treatment. However, much work is still required to clarify the mechanism of action of effective stem cell therapy, type of stem cell therapy, optimal timing of therapy initiation, combination of cocurrent medical treatment and patient selection criteria. This paper will focus on stem cell therapy in children with traumatic brain injury.
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Lesiones Traumáticas del Encéfalo , Trasplante de Células Madre Mesenquimatosas , Humanos , Niño , Lesiones Traumáticas del Encéfalo/terapia , Trasplante de Células Madre , CogniciónRESUMEN
BACKGROUND: Chronic limb-threatening ischemia (CLTI) represents the final stage of peripheral arterial disease. Approximately one-third of patients with CLTI are not eligible for conventional surgical treatments. Furthermore, patients with advanced stage of CLTI are prone to amputation and death. Thus, an effective therapeutic strategy is urgently needed. In this context, autologous bone marrow mononuclear cell (auto-BM-MNC) and allogeneic mesenchymal stem cells represent a promising therapeutic approach for treating CLTI. In this study, we compared the safety and beneficial therapeutic effect of auto-BM-MNC versus allogeneic Wharton jelly-derived mesenchymal stem cells (allo-WJ-MSCs) in diabetic patients with CLTI. METHODS: We performed a randomized, prospective, double-blind and controlled pilot study. Twenty-four diabetic patients in the advanced stage of CLTI (4 or 5 in Rutherford's classification) and a transcutaneous oxygen pressure (TcPO2) below 30 mmHg were randomized to receive 15 injections of (i) auto-BM-MNC (7.197 × 106 ± 2.984 × 106 cells/mL) (n = 7), (ii) allo-WJ-MSCs (1.333 × 106 cells/mL) (n = 7) or (iii) placebo solution (1 mL) (n = 10), which were administered into the periadventitial layer of the arterial walls under eco-Doppler guidance. The follow-up visits were at months 1, 3, 6, and 12 to evaluate the following parameters: (i) Rutherford's classification, (ii) TcPO2, (iii) percentage of wound closure, (iv) pain, (v) pain-free walking distance, (vi) revascularization and limb-survival proportion, and (vii) life quality (EQ-5D questionnaire). RESULTS: No adverse events were reported. Patients with CLTI who received auto-BM-MNC and allo-WJ-MSCs presented an improvement in Rutherford's classification, a significant increase in TcPO2 valuesâ¬, a reduction in the lesion size in a shorter time, a decrease in the pain score and an increase in the pain-free walking distance, in comparison with the placebo group. In addition, the participants treated with auto-BM-MNC and allo-WJ-MSCs kept their limbs during the follow-up period, unlike the placebo group, which had a marked increase in amputation. CONCLUSIONS: Our results showed that patients with CLTI treated with auto-BM-MNC and allo-WJ-MSCs conserved 100% of their limb during 12 months of the follow-up compared to the placebo group, where 60% of participants underwent limb amputation in different times. Furthermore, we observed a faster improvement in the allo-WJ-MSC group, unlike the auto-BM-MNC group. Trial registration This study was retrospectively registered at ClinicalTrials.gov (NCT05631444).
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Diabetes Mellitus , Células Madre Mesenquimatosas , Gelatina de Wharton , Humanos , Isquemia Crónica que Amenaza las Extremidades , Médula Ósea , Estudios ProspectivosRESUMEN
Hydrogen (H2) is a major biodegradation product of implanted magnesium (Mg) alloys that are commonly used in the healing of bone fractures. Our earlier study showed that H2 can inhibit mouse bone marrow mononuclear cell (BMMC) osteoclastogenesis during the differentiation of these cells into osteoclasts, thereby facilitating fracture healing. However, the way by which H2 inhibits osteoclastogenesis remains to be elucidated. The present study used RNA-sequencing to study the transcriptome of H2-exposed BMMCs in an osteoclast-induced environment and identified the target genes and signaling pathways through which H2 exerts its biological effects. Several upregulated genes were identified: Fos, Dusp1, Cxcl1, Reln, Itga2b, Plin2, Lif, Thbs1, Vegfa and Gadd45a. Several downregulated genes were also revealed: Hspa1b, Gm4951, F830016B08Rik, Fads2, Hspa1a, Slc27a6, Cacna1b, Scd2, Lama3 and Col4a5. These differentially expressed genes were mainly involved in osteoclast differentiation cascades, as well as PI3K-AKT, Forkhead box O (FoxO), MAPK, peroxisome proliferator-activated receptor (PPAR), TNF, TGF-ß, JAK-STAT, RAS, VEGF, hypoxia-inducible factor (HIF-1) and AMPK signaling pathways. In summary, the present study revealed the key genes and signaling pathways involved in the H2-mediated inhibition of osteoclastogenesis, thereby providing a theoretical basis for the significance of H2 and an experimental basis for the application of Mg alloys in the treatment of osteoporosis.
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OBJECTIVES: Platelet-rich fibrin (PRF) and bone marrow mononuclear cells are potential scaffolds and cell sources for osteochondral regeneration. The main aim of this paper is to examine the effects of PRF scaffolds and autologous uncultured bone marrow mononuclear cells on osteochondral regeneration in rabbit knees. MATERIALS AND METHODS: Three different types of PRF scaffolds were generated from peripheral blood (Ch-PRF and L-PRF) and bone marrow combined with uncultured bone marrow mononuclear cells (BMM-PRF). The histological characteristics of these scaffolds were assessed via hematoxylin-eosin staining, PicroSirius red staining, and immunohistochemical staining. Osteochondral defects with a diameter of 3 mm and depth of 3 mm were created on the trochlear groove of the rabbit's femur. Different PRF scaffolds were then applied to treat the defects. A group of rabbits with induced osteochondral defects that were not treated with any scaffold was used as a control. Osteochondral tissue regeneration was assessed after 2, 4, and 6 weeks by macroscopy (using the Internal Cartilage Repair Society score, X-ray) and microscopy (hematoxylin-eosin stain, safranin O stain, toluidine stain, and Wakitani histological scale, immunohistochemistry), in addition to gene expression analysis of osteochondral markers. RESULTS: Ch-PRF had a heterogeneous fibrin network structure and cellular population; L-PRF and BMM-PRF had a homogeneous structure with a uniform distribution of the fibrin network. Ch-PRF and L-PRF contained a population of CD45-positive leukocytes embedded in the fibrin network, while mononuclear cells in the BMM-PRF scaffold were positive for the pluripotent stem cell-specific antibody Oct-4. In comparison to the untreated group, the rabbits that were given the autologous graft displayed significantly improved healing of the articular cartilage tissue and of the subchondral bone. Regeneration was gradually observed after 2, 4, and 6 weeks of PRF scaffold treatment, which was particularly evident in the BMM-PRF group. CONCLUSIONS: The combination of biomaterials with autologous platelet-rich fibrin and uncultured bone marrow mononuclear cells promoted osteochondral regeneration in a rabbit model more than platelet-rich fibrin material alone. Our results indicate that autologous platelet-rich fibrin scaffolds combined with uncultured bone marrow mononuclear cells applied in healing osteochondral lesions may represent a suitable treatment in addition to stem cell and biomaterial therapy.
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Introduction: Retinopathy of prematurity (ROP) is a vasoproliferative disease that alters retinal vascular patterns in preterm neonates with immature retinal vasculature. This study was conducted to investigate the effects of cell therapy by bone marrow mononuclear cells (BMMNC) on neurological and vascular damages in a rat model of ROP. Methods: Ten newborn Wistar rats were divided randomly into the control and the oxygen-induced retinopathy (OIR) groups. Animals in the OIR group were incubated in an oxygen chamber to induce retinopathy. One eye of animals in the OIR group received BMMNC suspension (treated eyes), and the contralateral eye received the same volume of saline injection. Then, all animals underwent funduscopy, angiography, electroretinography, histopathology and immunohistochemical assessments. Results: Compared to the saline injection group, eyes treated with BMMNC had less vascular tortuosity while veins and arteries had relatively the same caliber, as revealed by fundus examinations. Eyes in the treatment group showed significantly elevated photopic and scotopic B waves amplitude. Neovascularization in the inner retinal layer and apoptosis of neural retina cells in the treatment group was significantly lower compared to untreated eyes. Also, BMMNC transplantation decreased glial cell activation and VEGF expression in ischemic retina. Conclusions: Our results indicate that intravitreal injection of BMMNC reduces neural and vascular damages and results in recovered retinal function in rat model of ROP. Ease of extraction without in vitro processing, besides the therapeutic effects of BMMNCs, make this source of cells as a new choice of therapy for ROP or other retinal ischemic diseases.
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BACKGROUND: To evaluate the safety and efficacy of autologous bone marrow mononuclear cell (BMMNC) infusion in the management of neurological sequelae in children with spina bifida (SB). METHODS: BMMNCs were harvested from bilateral anterior iliac crests. Two intrathecal BMMNC administrations were performed with an interval of 6 months. The measurements of outcomes included clinical assessments, cystomanometry and rectomanometry. RESULTS: Eleven children with SB underwent autologous BMMNC infusions from 2016 to 2020. There were no severe adverse events during the study period. The number of patients requiring assistance to expel stools decreased from 11 before cell infusion to 3 after the second cell infusion. The number of patients who had urine leakage decreased from 9 patients at baseline to 3 patients after the second BMMNC infusion. The mean bladder capacity increased from 127.7 ± 59.2 ml at baseline to 136.3 ± 54.8 ml at six months and to 158.3 ± 56.2 ml at 12 months after BMMNC infusions. Detrusor pressure (pdet) decreased from 32.4 ± 22.0 cm H2O at baseline to 21.9 ± 11.8 cm H2O after 12 months of follow-up. At baseline, six patients could walk independently. After the 2nd infusion, eight patients could walk independently. CONCLUSION: Intrathecal infusions of autologous bone marrow mononuclear cells are safe and may improve bowel, bladder, and motor function in children with SB. TRIAL REGISTRATION: NCT, NCT05472428. Registered July 25, 2022- Retrospectively registered, https://www. CLINICALTRIALS: gov/ct2/show/NCT05472428 .
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Médula Ósea , Disrafia Espinal , Humanos , Niño , Vejiga Urinaria , Trasplante de Médula Ósea , Disrafia Espinal/complicaciones , Disrafia Espinal/terapiaRESUMEN
PURPOSE: This study aimed to investigate the efficacy and safety of autologous platelet-rich plasma (PRP) and bone marrow mononuclear cells (BMMCs) grafting combined with core decompression (CD) in the treatment of Association Research Circulation Osseous (ARCO) II-IIIA stage non-traumatic osteonecrosis of the femoral head (ONFH). METHODS: The clinical data of 44 patients (44 hips) with non-traumatic ONFH from December 2018 to December 2019 were retrospectively reviewed. Twenty-four patients underwent CD combined with autologous PRP and BMMCs grafting (PRP+BMMCs group), and 20 patients underwent core decompression alone (CD group). During a minimum follow-up of 36 months, radiographic outcomes were evaluated using X-ray, radiographic failure rates were compared, and Harris hip score (HHS) and visual analog scale (VAS) were selected to evaluate clinical outcomes. The percentage of patients with minimal clinically important difference (MCID) in both groups was analyzed. Clinical failure was defined as further total hip arthroplasty (THA) with Kaplan-Meier survival analysis. Surgical complications were recorded. RESULTS: All patients had well healed wounds, and no complications such as infection and thrombosis occurred. HHS and VAS scores in both the PRP+BMMCs and CD groups were better than those preoperatively (P<0.05). At the last follow-up, the HHS and VAS scores of the PRP+BMMCs group were significantly better than those of the CD group (P<0.05). In ARCO II-IIIA stage, 66.7% of the PRP+BMMCs group and 30.0% of the CD group achieved the MCID (P<0.05). The clinical and imaging failure rates in the PRP+BMMCs group were 12.5% and 20.8%, respectively, compared with 40.0% and 50.0% in the CD group (P<0.05). In ARCO II stage, the MCID, clinical and imaging failure rates of PRP+BMMCs group and CD group were 66.7% and 33.3% (P<0.05), 4.8% and 33.3% (P<0.05), 14.3% and 44.4% (P<0.05), respectively. The PRP+BMMCs group had better hip survival rate compared with CD group (P<0.05). CONCLUSION: CD combined with autologous PRP and BMMCs grafting is a safe and effective method for the treatment of ARCO II-IIIA stage non-traumatic ONFH, especially for ARCO II stage, effectively reducing the collapse rate of the femoral head and delaying or even avoiding THA.
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Necrosis de la Cabeza Femoral , Plasma Rico en Plaquetas , Humanos , Resultado del Tratamiento , Estudios Retrospectivos , Cabeza Femoral/cirugía , Médula Ósea/cirugía , Necrosis de la Cabeza Femoral/cirugía , Descompresión Quirúrgica/métodos , Trasplante ÓseoRESUMEN
PURPOSE: Heart failure (HF) is a major complication of acute myocardial infarction (AMI). Transplantation of bone marrow mononuclear cells (BM-MNC) in the setting of AMI has been proposed as a means for myocardial tissue regeneration. Several trials have explored the outcomes of these cells on surrogate end points such as left ventricular ejection fraction (LVEF) in patients with AMI. However, the data regarding the clinical efficacy are infrequent. Here, we performed a meta-analysis investigating the effect of BM-MNCs injection on the rate of hospitalization for HF in the long-term follow-up period. METHODS: PubMed, Scopus, and Cochrane databases were queried with various combinations of keywords through May 2, 2022. A random-effects meta-analysis was performed to calculate risk ratio (RR) and 95% confidence interval (CI) of hospitalization for HF, all-cause mortality, and stroke rate. Subgroup analyses for hospitalization based on time and cell dose were performed. RESULTS: A total of 2150 patients with AMI across 22 trials were included for quantitative synthesis. At long-term follow-up, AMI patients treated with an intracoronary injection of BM-MNCs were less likely to be hospitalized for heart failure compared to the control group receiving standard treatment (RR = 0.54, 95% CI = [0.37; 0.78], p = 0.002). There was no association between BM-MNC therapy and all-cause mortality (RR = 0.69, 95% CI = [0.47; 1.01], p = 0.05) and stroke (RR = 1.12, 95% CI= [0.24; 5.21], p = 0.85). CONCLUSION: Autologous injection of BM-MNC in the setting of AMI may be associated with decreased risk of hospitalization of heart failure in the long term. However, its effect on all-cause mortality and stroke rate is questionable.
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Insuficiencia Cardíaca , Infarto del Miocardio , Accidente Cerebrovascular , Humanos , Volumen Sistólico , Médula Ósea , Función Ventricular Izquierda , Ensayos Clínicos Controlados Aleatorios como Asunto , Infarto del Miocardio/terapia , Resultado del Tratamiento , Trasplante de Células , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/terapiaRESUMEN
We studied the effect of preconditioning of human bone marrow mononuclear cells with erythropoietin on the immunophenotype of immunocompetent cells and paracrine activity of mouse splenocytes. The expression of erythropoietin receptors on immunocompetent human bone marrow cells was shown to change after a short-term (60 min) exposure to erythropoietin. The number of T helpers carrying erythropoietin receptors decreased and the number of T suppressors, B lymphocytes, and monocytes carrying erythropoietin receptors increased. The presence of 30% conditioned medium from human bone marrow mononuclear cells or 33.4 U/ml of erythropoietin reduced apoptosis/necrosis, increased intracellular activity of NADPH-dependent oxidoreductases of splenocytes, and did not affect oxidative phosphorylation (did not enhance lactate production and glucose uptake by cells).