“…After preliminary screening a total of 358 citations were pulled for full text review; 54 publications met our pre-defined eligibility criteria and were included in the review ( Fig 1 )[ 7 , 10 – 62 ] These reported 70 experiments ( Table 1 , S1 File , S1 Table ), of which 21(from 17 publications) reported our primary outcome death and were included in the meta-analysis. [ 7 , 10 , 15 – 18 , 29 , 31 , 32 , 34 , 37 , 41 , 43 , 44 , 46 , 47 , 59 ]…”
The Acute Respiratory Distress Syndrome (ARDS) is a devastating clinical condition that is associated with a 30–40% risk of death, and significant long term morbidity for those who survive. Mesenchymal stromal cells (MSC) have emerged as a potential novel treatment as in pre-clinical models they have been shown to modulate inflammation (a major pathophysiological hallmark of ARDS) while enhancing bacterial clearance and reducing organ injury and death. A systematic search of MEDLINE, EMBASE, BIOSIS and Web of Science was performed to identify pre-clinical studies that examined the efficacy MSCs as compared to diseased controls for the treatment of Acute Lung Injury (ALI) (the pre-clinical correlate of human ARDS) on mortality, a clinically relevant outcome. We assessed study quality and pooled results using random effect meta-analysis. A total of 54 publications met our inclusion criteria of which 17 (21 experiments) reported mortality and were included in the meta-analysis. Treatment with MSCs, as compared to controls, significantly decreased the overall odds of death in animals with ALI (Odds Ratio 0.24, 95% Confidence Interval 0.18–0.34, I2 8%). Efficacy was maintained across different types of animal models and means of ALI induction; MSC origin, source, route of administration and preparation; and the clinical relevance of the model (timing of MSC administration, administration of fluids and or antibiotics). Reporting of standard MSC characterization for experiments that used human MSCs and risks of bias was generally poor, and although not statistically significant, a funnel plot analysis for overall mortality suggested the presence of publication bias. The results from our meta-analysis support that MSCs substantially reduce the odds of death in animal models of ALI but important reporting elements were sub optimal and limit the strength of our conclusions.
“…After preliminary screening a total of 358 citations were pulled for full text review; 54 publications met our pre-defined eligibility criteria and were included in the review ( Fig 1 )[ 7 , 10 – 62 ] These reported 70 experiments ( Table 1 , S1 File , S1 Table ), of which 21(from 17 publications) reported our primary outcome death and were included in the meta-analysis. [ 7 , 10 , 15 – 18 , 29 , 31 , 32 , 34 , 37 , 41 , 43 , 44 , 46 , 47 , 59 ]…”
The Acute Respiratory Distress Syndrome (ARDS) is a devastating clinical condition that is associated with a 30–40% risk of death, and significant long term morbidity for those who survive. Mesenchymal stromal cells (MSC) have emerged as a potential novel treatment as in pre-clinical models they have been shown to modulate inflammation (a major pathophysiological hallmark of ARDS) while enhancing bacterial clearance and reducing organ injury and death. A systematic search of MEDLINE, EMBASE, BIOSIS and Web of Science was performed to identify pre-clinical studies that examined the efficacy MSCs as compared to diseased controls for the treatment of Acute Lung Injury (ALI) (the pre-clinical correlate of human ARDS) on mortality, a clinically relevant outcome. We assessed study quality and pooled results using random effect meta-analysis. A total of 54 publications met our inclusion criteria of which 17 (21 experiments) reported mortality and were included in the meta-analysis. Treatment with MSCs, as compared to controls, significantly decreased the overall odds of death in animals with ALI (Odds Ratio 0.24, 95% Confidence Interval 0.18–0.34, I2 8%). Efficacy was maintained across different types of animal models and means of ALI induction; MSC origin, source, route of administration and preparation; and the clinical relevance of the model (timing of MSC administration, administration of fluids and or antibiotics). Reporting of standard MSC characterization for experiments that used human MSCs and risks of bias was generally poor, and although not statistically significant, a funnel plot analysis for overall mortality suggested the presence of publication bias. The results from our meta-analysis support that MSCs substantially reduce the odds of death in animal models of ALI but important reporting elements were sub optimal and limit the strength of our conclusions.
“…Following deduplication and screening, 18 studies were included in the review (Figure 1). These studies were published over a six year period (2009 to 2015) and corresponded to 20 unique experiments and involved a total of 980 animals (Table 1) (Bi et al., 2010; Chang et al, 2012; Chao et al., 2014; Gonzalez-Rey et al, 2009; Hall et al, 2013; Kim et al, 2014; Krasnodembskaya et al, 2012; Li et al, 2012; Liang et al., 2011; Luo et al, 2014; Mei et al., 2010; Nemeth et al., 2009; Pedrazza et al, 2014; Sepúlveda et al, 2014; Yang et al, 2015; Zhao et al, 2013, 2014; Zhou et al, 2014). Six authors were contacted for additional information and all replied.10.7554/eLife.17850.003Figure 1.Preferred reporting items for systematic reviews and meta-analysis (PRISMA) flow diagram for study selection. DOI:
http://dx.doi.org/10.7554/eLife.17850.003…”
Section: Resultsmentioning
confidence: 99%
“…)NoneAdipose Xenogenic1.0 x 10 6 or3.0 x 10 5 0.5IPDMEMNemeth et al. (2009)
United StatesMouse C57BL/6, MCLP (2 × 21 G)Fluid and antibioticsBone marrow Allogeneic1.0 × 10 6 0 or 1IVPBS or FibroblastBi et al (2010)
ChinaMouse C57BL/6, NRCLP (2 × 21 G)NoneBone marrow Xenogenic1.0 × 10 6 1 1IVPBSMei et al. (2010)A CanadaMouse C57BL/6J, FCLP (1 × 22 G)FluidBone marrow Syngeneic2.5 × 10 5 6IVNSMei et al.…”
Evaluation of preclinical evidence prior to initiating early-phase clinical studies has typically been performed by selecting individual studies in a non-systematic process that may introduce bias. Thus, in preparation for a first-in-human trial of mesenchymal stromal cells (MSCs) for septic shock, we applied systematic review methodology to evaluate all published preclinical evidence. We identified 20 controlled comparison experiments (980 animals from 18 publications) of in vivo sepsis models. Meta-analysis demonstrated that MSC treatment of preclinical sepsis significantly reduced mortality over a range of experimental conditions (odds ratio 0.27, 95% confidence interval 0.18–0.40, latest timepoint reported for each study). Risk of bias was unclear as few studies described elements such as randomization and no studies included an appropriately calculated sample size. Moreover, the presence of publication bias resulted in a ~30% overestimate of effect and threats to validity limit the strength of our conclusions. This novel prospective application of systematic review methodology serves as a template to evaluate preclinical evidence prior to initiating first-in-human clinical studies.DOI:
http://dx.doi.org/10.7554/eLife.17850.001
“…Bone marrow-derived stromal cells (BMSCs) have potent immunosuppressive effects in humans in vivo. Bi LiangKuan and colleagues (Sun Yat-sen University) showed that systemic delivery of IL-10 by BMSCs may serve as a potential treatment in sepsis therapy [17].…”
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