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Efficacy of mesenchymal stromal cells intraspinal transplantation for patients with different degrees of spinal cord injury: A systematic review and meta-analysis
Several studies have reported that mesenchymal stromal cells (MSCs) may improve neurological functions in patients with spinal cord injury (SCI). In this study, we conducted a systematic review and meta-analysis to summarize the effects of MSC treatment on different degrees of severity of SCI.
Methods
Systematic searching of studies reporting outcomes of MSCs on specific injury severities of patients with SCI was performed in The National Library of Medicine (MEDLINE), Embase and Cochrane for published articles up to the 6 July 2022. Two investigators independently reviewed the included studies and extracted the relevant data. The standardized mean differences of American Spinal Injury Association (ASIA) motor score, ASIA light touch scores, ASIA pinprick scores and the Barthel index between baseline and follow-ups were pooled.
Results
A total of eight studies were included. A large majority focused on patients with ASIA grade A classification. The pooled mean differences of ASIA motor scores, ASIA light touch scores, ASIA pinprick scores and the Barthel index were –2.78 (95% confidence interval [CI] –5.12 to –0.43, P = 0.02), –18.26 (95% CI –26.09 to –10.43, P < 0.01), –17.08 (95% CI –24.10 to –10.07, P < 0.01) and –4.37 (95% CI –10.96 to 2.22, P = 0.19), respectively.
Conclusions
MSC transplantation was a significantly effective therapy for patients with SCI with ASIA grade A. In the future, further studies are warranted to confirm the potential beneficial effects of MSC therapy.
Spinal cord injury (SCI) is a debilitating condition and a potentially devastating event for the central nervous system that may lead to the loss of sensory and motor functions below the damaged segment, producing a huge physical burden for patients [
]. The prevalence of SCI worldwide involves a conservative estimate of 250,000–500,000 people annually, values that are gradually increasing, with the growing numbers of people using modern transportation together with an aging population [
In past decades, treatments for SCI have included surgical decompression, hemodynamic therapy, corticosteroids and invasive spinal cord pressure monitoring [
A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study.
]. Human umbilical cord MSCs, endowed with faster self-renewal and lower immunogenicity than other sources of MSCs, hold great promise for SCI repair [
] have reported that the autologous MSCs therapeutic approach improved neurological functions in patients with SCI according to the American Spinal Injury Association (ASIA) impairment scale grade, ASIA motor score, ASIA sensory functional score and the Barthel index.
Recently, several studies have been conducted to explore the impact of MSCs in patients with various degrees of severity of SCI and found that MSCs have a significant impact on functional improvement and recovery in patients with chronic SCI [
Safety and neurological assessments after autologous transplantation of bone marrow mesenchymal stem cells in subjects with chronic spinal cord injury.
]. However, no systematic review has summarized the treatment effects of MSCs according to the severity of SCI cases. Given the lack of conclusive evidence in this regard, in the present study the aims were to review systematically the available literature on the impact of MSCs on SCI in patients with various degrees of severity and to perform a meta-analysis of the available data.
Methods
Ethics
Ethics approval and consent to participate were not applicable.
Search strategy
This systematic review and meta-analysis were performed and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist [
]. Systematic searches were conducted in PubMed, Embase and the Cochrane Central Register of Controlled Trials for potential studies without any language restrictions from their inception to 16 January 2022. The major search terms were as follows: “mesenchymal stromal cells,” “MSCs,” “spinal cord injury” and “SCI.” The detailed search strategies are given in supplementary File 1. Reference lists of review articles, relevant studies and clinical practice guidelines also were interrogated on the Google Scholar website for previously reviewed papers.
Inclusion and exclusion criteria
Two authors independently reviewed the titles and abstracts of the studies retrieved from the databases. Full-text articles of studies considered potentially relevant were obtained and reviewed for eligibility by both authors. Disagreement on the inclusion of a full-text article was discussed with an independent arbiter, and any reasons for exclusion of full texts were collated.
The PICO (population, interventions, comparators, outcomes) criteria for the eligibility of studies were used to determine inclusion and exclusion criteria:
Exclusion criteria were as follows:
•
Patients: SCI with the same ASIA score.
•
Intervention: MSCs.
•
Comparators: before and after MSCs.
•
Outcomes: ASIA motor score, ASIA light touch score, ASIA pinprick score, residual urine volume and the Barthel index.
Exclusion criteria were as follows:
•
Necessary data could not be extracted from the original articles.
•
Duplicate publications (only the most informative and complete data were analyzed).
•
Studies lacked original patient data, reviews, letters, editorial comments, meeting abstracts, replies from authors and case reports (≤10 cases).
•
Studies published in a language other than English.
Data extraction
All potential papers were downloaded into citation software EndNote and duplicates deleted. Then, the titles and abstracts were screened to identify studies that potentially met the eligibility criteria. Finally, full texts were assessed for eligibility. Data extraction and assessment of risk of bias were conducted independently by the two authors using a standardized data extraction form constructed in Microsoft Excel (Microsoft Corp., Redmond, WA). For the meta-analyses, the first author, country, duration of follow-up, number of patients, age, sex, details of intervention and outcomes were collected.
Risk of bias and quality assessment of the selected studies
Only observational studies were included and the assessment of the study quality was evaluated using the Newcastle–Ottawa Scale [
Wells G, Shea B, O'Connell D, Peterson J, Welch V, Loso M, Tugwell P, The Newcastle Ottawa Scale (NOS) for assessing the quality of non-randomised studies in meta-analysis. Oxford: University of Ottawa; 2000.
]. Two authors (CM and XW) independently evaluated the included studies and disagreement were resolved by discussion to produce final agreed scores. Using this tool, three domains were assessed: (i) selection of study groups (four points); (ii) comparability of groups (two points); and (iii) ascertainment of exposure and outcomes (three points) for case–control and cohort studies, respectively.
Data analysis
An overall meta-analysis was performed if there were two or more estimates irrespective of the study design. The effect sizes were calculated as the standardized mean differences (MDs) between the baseline and follow-up. Effect sizes assessed before and after intervention from each study were pooled using a random-effects model [
]. Statistically significant differences were determined using P values from the pooled fold changes. The Cochran's Q statistics and the associated test were calculated to evaluate between-study heterogeneity. In addition to Cochran's Q, I2 values were calculated. For greater values of the I2 index (an I2 index of 30% and 75% corresponded to medium and high heterogeneity, respectively), sensitivity analysis was conducted to explore the source of heterogeneity. The Begg rank correlation [
] were employed to assess publication bias (P < 0.05 was considered indicative of a statistically significant publication bias). Review Manager (Version 5.3, The Cochrane Collaboration, Oxford, UK) was used for the generation of forest plots and statistical analyses. Begg and Egger tests were conducted using STATA 15.0 (Stata Corporation, College Station, TX, USA). A two-side P value < 0.05 was considered to indicate a statistically significant difference.
Results
Literature search and characteristics of the selected studies
As shown in Figure 1, from the combination of three searches, our initial search identified 2539 records. After removing duplicates, 1560 records remained. We then reviewed the titles and abstracts leading to 1469 irrelevant articles being excluded. Ultimately, a total of eight studies [
Safety and neurological assessments after autologous transplantation of bone marrow mesenchymal stem cells in subjects with chronic spinal cord injury.
A prospective randomized double-blind clinical trial using a combination of olfactory ensheathing cells and Schwann cells for the treatment of chronic complete spinal cord injuries.
The characteristics of the included studies are summarized in Table 1, which were published between 2012 and 2016, with samples ranging from 11 to 50. The studies were conducted in multiple countries thus: China (n = 3), USA (n = 1), Egypt (n = 1), Brazil (n = 1), Korea (n = 1) and Spain (n = 1). The majority of the patients were male adults with ASIA grade A SCI.
Safety and neurological assessments after autologous transplantation of bone marrow mesenchymal stem cells in subjects with chronic spinal cord injury.
The overall risk of bias and the quality of the included studies are presented in supplementary Table 1. None of the included studies was judged to have low quality, and most studies were awarded ≥6 stars.
ASIA motor scores
Figure 2 presents the pooled ASIA motor scores. Six studies reported that the hospital ASIA motor score and the MDs among the two groups ranged from –10.50 to 0. When pooling these scores, we found that the pooled MD was –2.78 (95% confidence interval [CI] –5.12 to –0.43, P = 0.02) with moderate heterogeneity (I2 = 32%). A funnel plot of the studies reported ASIA motor scores is shown in supplementary Figure 1.
Fig. 2Summarized mean differences of ASIA motor scores between baseline and follow-up. IV, inverse variance; SD, standard deviation.
Similarly, six studies reported the ASIA light touch scores, which ranged from –31.90 to –5.40 (Figure 3a). The pooled MD of ASIA light touch score (–18.26, 95% CI 26.09 to –10.43) was statistically significant, with a P value < 0.01 and with significant heterogeneity (I2 = 90%). These findings indicated that the improvements in the ASIA light touch score was increased after MSC transplantation (Figure 3a). A funnel plot of the studies that reported ASIA motor scores is presented in supplementary Figure 2.
Fig. 3Summarized mean differences of ASIA light touch scores between the experimental and control groups a, summarized mean differences of ASIA light touch scores between the experimental and control groups; b, sensitivity analysis for exploring heterogeneity. IV, inverse variance; SD, standard deviation.
], a moderate but significantly decreased heterogeneity was seen (I2 = 34%, Figure 3b). The pooled MD of ASIA light touch scores was significant between baseline and follow-up (MD = –16.52, P < 0.01).
ASIA pinprick scores
Figure 4a and supplementary Figure 3 show forest and funnel plot ASIA pinprick scores, respectively. Six studies reported ASIA pinprick scores and the pooled MD was -17.08 (95% CI –24.10 to –10.07, P < 0.01), with significant heterogeneity (I2 = 87%).
Fig. 4Summarized mean differences of ASIA pinprick scores between experimental and control groups a, summarized mean differences of ASIA pinprick scores between experimental and control groups; b, sensitivity analysis for exploring heterogeneity. IV, inverse variance; SD, standard deviation.
] were excluded, no heterogeneity (I2 = 21%, Figure 4b) was detected and a similar pooled MD was found (MD = –15.60, P < 0.01). From these analyses, we can confirm that MSC treatment would induce sensory pain from the injury of the spinal cord.
Residual urine volume
Of the included studies, three reported residual urine volume changes from baseline and at follow-up (Figure 5). Significantly increased urine output was measured with the pooled MD volumes of –72.17 mL (95% CI –108.71 to –35.63, P < 0.01) without heterogeneity (I2 = 11%). A funnel plot of the studies that reported residual urine volumes is shown in supplementary Figure 4.
Fig. 5Summarized mean differences of residual urine volumes between the experimental and control groups. IV, inverse variance; SD, standard deviation.
As shown in Figure 6, two studies reported the Barthel index. After pooling the results, no statistically significant change was detected with MD –4.37 (95% CI –10.96 to 2.22, P = 0.19). A funnel plot of studies that reported the Barthel index is shown in supplementary Figure 5.
Fig. 6Summarized mean differences of the Barthel index between the experimental and control groups. IV, inverse variance; SD, standard deviation.
There was no publication bias according to both Begg's (P > 0.05) and Egger's (P > 0.05) tests. The detailed potential publication bias is given in supplementary Table 2.
Discussion
In the current study, we first systematically reviewed and summarized the effect of MSCs in SCI according to the severity of the cases. In our study, eight papers with 11 studies were included and summarized. It is evident that ASIA grade A SCI cases may significantly benefit from MSCs in ASIA light touch scores, ASIA pinprick scores, residual urine volume and the Barthel index.
] evaluated the safety and efficacy of MSCs in treating patients with SCI as well as the optimal source and transplantation method. They reported that pooled ASIA motor and Barthel index values were 2.04 (95% CI 1.62–2.45, P < 0.01) and 0.41 (95% CI 0.08–0.74, P < 0.01), respectively. A study by Muthu et al. [
] also pooled the efficacy of MSCs in treating patients with SCI and reported that the pooled MD of residual urine volume was –36.55 (95% CI –68.105 to –4.994, P = 0.023). In the present study, we observed a slightly greater MD of ASIA motor, Barthel index and residual urine volumes.
Cell therapy using MSCs is currently one of the most dynamically developing branches of regenerative medicine. The primary pathological changes arising after spinal injury include disruption of axons and blood vessels, disturbance of local ionic concentrations, loss of blood pressure regulation, reduced blood flow through the spinal cord and damage to the regeneration process. The beneficial effects of MSCs transplantation in SCI have been shown in different experimental studies after intrathecal, intracerebral or intravenous cell infusions. However, studies have reported that the therapeutic competence of MSCs increase more efficiently if they are infused directly into the injury site [
]. Studies have reported that MSCs are attracted to the area of damage by various diverse chemokines, such as platelet-derived growth factor-AB, stromal-derived factor-1 and macrophage-derived chemokine [
Involvement of various chemokine/chemokine receptor axes in trafficking and oriented locomotion of mesenchymal stem cells in multiple sclerosis patients.
]. A similar finding was reported when MSCs were administered systemically. An effective and simple MSCs transplantation method is therefore local injection into the damaged area or closely surrounding healthy tissue [
]. In addition to neuronal restoration in SCI models, MSCs also have been shown to have an immunomodulatory effect, lessening the disease’s pro‐inflammatory reactions [
]. Although MSCs have been demonstrated to have a capability of improving anatomical and locomotor recovery after SCI, the post-injury inflammatory and toxic environment may not be suitable for the survival of grafted cells [
] reviewed the clinical applications of MSCs for the treatment of SCI and focused on the critical analysis of 17 clinical trials published thus far. It was concluded that the therapeutic use of MSCs is a safe treatment for patients with SCI in different phases and conditions. Although both the current study and the study that summarized 17 clinical trials published thus far observed positive results, more searches with a large scale are required to find the best cell source and transplantation protocol. Moreover, future studies that using standard evaluations, such as the ASIA scale, and other variables such as neurological recovery and quality of life, are needed to validate the findings of the present study.
There were several limitations to our systematic review. First, although the majority of the studies assessed the effects of MSCs in all SCI cases, we only pooled and summarized ASIA grade A SCI cases. Several important pieces of information were not available; thus, we could not perform a more accurate analysis or deploy more subgroup analysis. Second, although a comprehensive search strategy was independently performed by two investigators on three databases with cross-reviewing, we could not guarantee that all relevant studies were included in our analysis. Third, the majority of studies included necessarily investigated only a small number of SCI cases with the vast majority being males. The representativeness for SCI cases may therefore have been attenuated somewhat. Finally, a number of outcomes were assessed using various tools. Standardization of outcome reporting in future MSCs intervention trials will therefore be obligatory.
Conclusions
The review findings indicated that MSCs have an impact on the length of hospital stay and also significant therapeutic impacts on ASIA grade A cases. Despite the paucity of evidence in this population and the daunting challenges presented, further studies of MSCs treatments in other ASIA grade patients is clearly warranted, particularly given the absence of any documented evidence pointing to important clinical characteristics, and the devastating long-term consequences of SCI for patients.
Declaration of Competing Interest
CM, XW, WL, ZL, NL and YSX are the employees of Everunion Biotechnology Co. Ltd., Tianjin.
Funding
This study was supported by National Key Research and Development Project of Stem Cell and Transformation Research [grant number, 2019YFA0112100]. The funder of the individuals working on the study had no role in its design, data collection, data analysis, data interpretation or writing of the report.
Author contributions
Conception and design of the study: CM. Acquisition of data: ZL and WL. Analysis and interpretation of data: XW and WL. Drafting the article: CM, XW and YX. Revising the article critically for important intellectual content: WL, ZL and NL. All authors have approved the final article.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study.
Safety and neurological assessments after autologous transplantation of bone marrow mesenchymal stem cells in subjects with chronic spinal cord injury.
Wells G, Shea B, O'Connell D, Peterson J, Welch V, Loso M, Tugwell P, The Newcastle Ottawa Scale (NOS) for assessing the quality of non-randomised studies in meta-analysis. Oxford: University of Ottawa; 2000.
A prospective randomized double-blind clinical trial using a combination of olfactory ensheathing cells and Schwann cells for the treatment of chronic complete spinal cord injuries.
Involvement of various chemokine/chemokine receptor axes in trafficking and oriented locomotion of mesenchymal stem cells in multiple sclerosis patients.
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