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The Efficacy and Safety of Mesenchymal Stem Cell Transplantation for Spinal Cord Injury Patients: A Meta-Analysis and Systematic Review.

ABSTRACT: Spinal cord injury (SCI) is a devastating disease, with a high rate of disability. In this meta-analysis, we aimed to comprehensively assess the efficacy and safety of mesenchymal stem cells (MSCs) in treating clinical SCI patients. We systematically searched the PUBMED, EMBASE, Chinese Biomedical (CBM), Web of Science and Cochrane databases using the strategy of combination of free-text words and MeSH terms. The indicators of the American Spinal Injury Association (ASIA) impairment scale (AIS)-grading improvement rate and adverse effects were displayed with an overall relative risk (RR). For the continuous variables of the ASIA motor score, light-touch score, pinprick score, activities of daily living (ADL) score, and residual urine volume, we used odds ratio (OR) to analyze the data. Eleven studies comprising 499 patients meeting all inclusion and exclusion criteria were included. No serious heterogeneity or publication bias was observed across each study. The results showed that significant improvements of total AIS grade (RR: 3.70; P < 0.001), AIS grade A (RR: 3.57; P < 0.001), ASIA sensory score (OR: 8.63; P < 0.001) and reduction of residual urine volume (OR: -36.37; P = 0.03) were observed in experimental group compared with control group. However, no significant differences of motor score (OR: 1.37, P = 0.19) and ADL score (OR: 2.61, P = 0.27) were observed between experimental and control groups. In addition, there were no serious and permanent adverse effects after cell transplantation. Cell transplantation with MSCs is effective and safe in improving the sensory and bladder functions of SCI patients.

SUBMITTER: Xu P

PROVIDER: S-EPMC6322141 | biostudies-other | 2018 Oct

REPOSITORIES: biostudies-other

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The Efficacy and Safety of Mesenchymal Stem Cell Transplantation for Spinal Cord Injury Patients: A Meta-Analysis and Systematic Review.

Xu Panfeng P Yang Xianliang X

Cell transplantation 20181026 1

Spinal cord injury (SCI) is a devastating disease, with a high rate of disability. In this meta-analysis, we aimed to comprehensively assess the efficacy and safety of mesenchymal stem cells (MSCs) in treating clinical SCI patients. We systematically searched the PUBMED, EMBASE, Chinese Biomedical (CBM), Web of Science and Cochrane databases using the strategy of combination of free-text words and MeSH terms. The indicators of the American Spinal Injury Association (ASIA) impairment scale (AIS)- ...[more]

PMID: 30362373

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Project description:ObjectiveTo compare the safety and effectiveness of transplanted cells from different sources for spinal cord injury (SCI).DesignA systematic review and Bayesian network meta-analysis.Data sourcesMedline, Embase, and the Cochrane Central Register of Controlled Trials.Study selectionWe included randomized controlled trials, case-control studies, and case series related to cell transplantation for SCI patients, that included at least 1 of the following outcome measures: American Spinal Cord Injury Association (ASIA) Impairment Scale (AIS grade), ASIA motor score, ASIA sensory score, the Functional Independence Measure score (FIM), International Association of Neurorestoratology Spinal Cord Injury Functional Rating Scale (IANR-SCIFRS), or adverse events. Follow-up data were analyzed at 6 and 12 months.ResultsForty-four eligible trials, involving 1,266 patients, investigated 6 treatments: olfactory ensheathing cells (OECs), neural stem cells/ neural progenitor cells (NSCs), mesenchymal stem cells (MSCs), Schwann cells, macrophages, and combinations of cells (MSCs plus Schwann cells). Macrophages improved the AIS grade at 12 months (mean 0.42, 95% credible interval: 0-0.91, low certainty) and FIM score at 12 months (42.83, 36.33-49.18, very low certainty). MSCs improved the AIS grade at 6 months (0.42, 0.15-0.73, moderate certainty), the motor score at 6 months (4.43, 0.91-7.78, moderate certainty), light touch at 6 (10.01, 5.81-13.88, moderate certainty) and 12 months (11.48, 6.31-16.64, moderate certainty), pinprick score at 6 (14.54, 9.76-19.46, moderate certainty) and 12 months (12.48, 7.09-18.12, moderate certainty), and the IANR-SCIFRS at 6 (3.96, 0.62-6.97, moderate certainty) and 12 months (5.54, 2.45-8.42, moderate certainty). OECs improved the FIM score at 6 months (9.35, 1.71-17.00, moderate certainty). No intervention improved the motor score significantly at 12 months. The certainty of other interventions was low or very low. Overall, the number of adverse events associated with transplanted cells was low.ConclusionsPatients with SCI who receive transplantation of macrophages, MSCs, NSCs, or OECs may have improved disease prognosis. MSCs are the primary recommendations. Further exploration of the mechanism of cell transplantation in the treatment of SCI, transplantation time window, transplantation methods, and monitoring of the number of transplanted cells and cell survival is needed.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/#recordDetails, identifier: CRD 42021282043.

Project description:Background Mesenchymal stem cells (MSCs) is an attractive candidate in regenerative research and clinical trials have assessed their therapeutic potential in different neurological conditions with disparate etiologies. In this systematic review, we aimed to assess safety and clinical effect of MSC treatment in traumatic spinal cord injury (TSCI), multiple sclerosis (MS) and ischemic stroke (IS). Methods A systematic search was performed 2021-12-10 in MEDLINE, EMBASE, Web of Science and Cochrane where clinical studies assessing MSC treatment in TSCI, MS or IS were included. Studies without control group were excluded for efficacy analysis, but included in the safety analysis. For efficacy, AIS score, EDSS score and mRS were used as clinical endpoints and assessed in a meta-analysis using the random effects model. Findings Of 5,548 identified records, 54 studies were included. Twenty-six studies assessed MSC treatment in TSCI, 14 in MS and nine in IS, of which seven, seven and five studies were controlled, respectively. There were seven serious adverse events (SAEs), of which four were related to the surgical procedure and included one death due to complications following the implantation of MSCs. Three SAEs were considered directly related to the MSC treatment and all these had a transient course. In TSCI, a meta-analysis showed no difference in conversion from AIS A to C and a trend toward more patients treated with MSCs improving from AIS A to B as compared to controls (p = 0.05). A subgroup analysis performed per protocol, showed more MSC treated patients improving from AIS A to C in studies including patients within 8 weeks after injury (p = 0.04). In MS and IS, there were no significant differences in clinical outcomes between MSC treated patients and controls as measured by EDSS and mRS, respectively. Interpretation MSC-treatment is safe in patients with TSCI, MS and IS, although surgical implantation of MSC led to one fatal outcome in TSCI. There was no clear clinical benefit of MSC treatment, but this is not necessarily a proof of inefficacy due to the low number of controlled studies. Future studies assessing efficacy of MSC treatment should aim to do this in randomized, controlled studies.

Project description:Spinal cord injury (SCI) is a devastating condition that causes substantial morbidity and mortality and for which no treatments are available. Stem cells offer some promise in the restoration of neurological function. We used systematic review, meta-analysis, and meta-regression to study the impact of stem cell biology and experimental design on motor and sensory outcomes following stem cell treatments in animal models of SCI. One hundred and fifty-six publications using 45 different stem cell preparations met our prespecified inclusion criteria. Only one publication used autologous stem cells. Overall, allogeneic stem cell treatment appears to improve both motor (effect size, 27.2%; 95% Confidence Interval [CI], 25.0%-29.4%; 312 comparisons in 5,628 animals) and sensory (effect size, 26.3%; 95% CI, 7.9%-44.7%; 23 comparisons in 473 animals) outcome. For sensory outcome, most heterogeneity between experiments was accounted for by facets of stem cell biology. Differentiation before implantation and intravenous route of delivery favoured better outcome. Stem cell implantation did not appear to improve sensory outcome in female animals and appeared to be enhanced by isoflurane anaesthesia. Biological plausibility was supported by the presence of a dose-response relationship. For motor outcome, facets of stem cell biology had little detectable effect. Instead most heterogeneity could be explained by the experimental modelling and the outcome measure used. The location of injury, method of injury induction, and presence of immunosuppression all had an impact. Reporting of measures to reduce bias was higher than has been seen in other neuroscience domains but were still suboptimal. Motor outcomes studies that did not report the blinded assessment of outcome gave inflated estimates of efficacy. Extensive recent preclinical literature suggests that stem-cell-based therapies may offer promise, however the impact of compromised internal validity and publication bias mean that efficacy is likely to be somewhat lower than reported here.

Project description:Currently, there is no effective strategy to promote functional recovery after a spinal cord injury. Collagen scaffolds can not only provide support and guidance for axonal regeneration, but can also serve as a bridge for nerve regeneration at the injury site. They can additionally be used as carriers to retain mesenchymal stem cells at the injury site to enhance their effectiveness. Hence, we hypothesized that transplanting human umbilical cord-mesenchymal stem cells on collagen scaffolds would enhance healing following acute complete spinal cord injury. Here, we test this hypothesis through animal studies and a phase I clinical trial. (1) Animal experiments: Models of completely transected spinal cord injury were established in rats and canines by microsurgery. Mesenchymal stem cells derived from neonatal umbilical cord tissue were adsorbed onto collagen scaffolds and surgically implanted at the injury site in rats and canines; the animals were observed after 1 week-6 months. The transplantation resulted in increased motor scores, enhanced amplitude and shortened latency of the motor evoked potential, and reduced injury area as measured by magnetic resonance imaging. (2) Phase I clinical trial: Forty patients with acute complete cervical injuries were enrolled at the Characteristic Medical Center of Chinese People's Armed Police Force and divided into two groups. The treatment group (n = 20) received collagen scaffolds loaded with mesenchymal stem cells derived from neonatal umbilical cord tissues; the control group (n = 20) did not receive the stem-cell loaded collagen implant. All patients were followed for 12 months. In the treatment group, the American Spinal Injury Association scores and activities of daily life scores were increased, bowel and urinary functions were recovered, and residual urine volume was reduced compared with the pre-treatment baseline. Furthermore, magnetic resonance imaging showed that new nerve fiber connections were formed, and diffusion tensor imaging showed that electrophysiological activity was recovered after the treatment. No serious complication was observed during follow-up. In contrast, the neurological functions of the patients in the control group were not improved over the follow-up period. The above data preliminarily demonstrate that the transplantation of human umbilical cord-mesenchymal stem cells on a collagen scaffold can promote the recovery of neurological function after acute spinal cord injury. In the future, these results need to be confirmed in a multicenter, randomized controlled clinical trial with a larger sample size. The clinical trial was approved by the Ethics Committee of the Characteristic Medical Center of Chinese People's Armed Police Force on February 3, 2016 (approval No. PJHEC-2016-A8). All animal experiments were approved by the Ethics Committee of the Characteristic Medical Center of Chinese People's Armed Police Force on May 20, 2015 (approval No. PJHEC-2015-D5).

Project description:The administration of stem cells holds promise as a potential therapy for spinal cord injury (SCI). Mesenchymal stem cells have advantages for clinical applications, since they can be easily obtained, are suitable for autologous transplantation and have been previously shown to induce regeneration of the spinal cord in experimental settings. Here we evaluated the feasibility, safety and potential efficacy of autologous transplantation of mesenchymal stem cells in subjects with chronic complete SCI.We conducted a phase I, non-controlled study in 14 subjects of both genders aging between 18 to 65 years, with chronic traumatic SCI (>6 months), at thoracic or lumbar levels, classified as American Spinal Injury Association (ASIA) A - complete injury. Baseline somatosensory evoked potentials (SSEP), spinal magnetic resonance imaging (MRI) and urodynamics were assessed before and after treatment. Pain rating was performed using the McGill Pain Questionnaire and a visual analogue score scale. Bone marrow-derived mesenchymal stem cells were cultured and characterized by flow cytometry, cell differentiation assays and G-band karyotyping. Mesenchymal stem cells were injected directly into the lesion following laminectomy and durotomy.Cell transplantation was an overall safe and well-tolerated procedure. All subjects displayed variable improvements in tactile sensitivity and eight subjects developed lower limbs motor functional gains, principally in the hip flexors. Seven subjects presented sacral sparing and improved American Spinal Injury Association impairment scale (AIS) grades to B or C - incomplete injury. Nine subjects had improvements in urologic function. One subject presented changes in SSEP 3 and 6 months after mesenchymal stem cells transplantation. Statistically significant correlations between the improvements in neurological function and both injury size and level were found.Intralesional transplantation of autologous mesenchymal stem cells in subjects with chronic, complete spinal cord injury is safe, feasible, and may promote neurological improvements.ClinicalTrials.gov NCT01325103 - Registered 28 March 2011.

Dataset Information

The Efficacy and Safety of Mesenchymal Stem Cell Transplantation for Spinal Cord Injury Patients: A Meta-Analysis and Systematic Review.

Publications

The Efficacy and Safety of Mesenchymal Stem Cell Transplantation for Spinal Cord Injury Patients: A Meta-Analysis and Systematic Review.

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