Evaluating mesenchymal stem cell therapy for sepsis with preclinical meta-analyses prior to initiating a first-in-human trial

Abstract

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.

Keywords: epidemiology; global health; human biology; medicine; mouse; preclinical; rat; sepsis; stem cells; systematic review; translation.

Figure 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

Figure 2.. Forest plot summarizing effects of mesenchymal stromal cell (MSC) therapy on mortality in preclinical models of sepsis and endotoxemia.

Point estimates (odds ratio) and 95% confidence intervals (CI) are depicted for individual studies; size of point estimate depicts relative contribution to pooled effect. A pooled meta-analytic summary (random effects model) of overall effect of MSC therapy on mortality is depicted by the diamond at the bottom of the plot (vertical points represent odds ratio point estimate and horizontal points represent 95% CIs). Heterogeneity is represented with the I² statistic. Data from Pedrazza et al. (2014) was included in total counts but not included in meta-analysis due to 100% mortality in both study arms. DOI: http://dx.doi.org/10.7554/eLife.17850.005

Figure 2—figure supplement 1.. Forest plot summarizing relationship of compatibility of donor mesenchymal stromal cell (MSC) with recipient animal (xenogenic vs syngeneic vs allogeneic vs autologous) on mortality in preclinical models of sepsis and endotoxemia.

Point estimates (odds ratio) and 95% confidence intervals (CI) are depicted for individual studies; size of point estimate depicts relative contribution to pooled effect. A pooled meta-analytic summary (random effects model) of overall effect is depicted by the diamond at the bottom of each subgroup (vertical points represent odds ratio point estimate and horizontal points represent 95% CIs). Heterogeneity is represented with the I² statistic. Data from Pedrazza et al 2014 was included in total counts but not included in meta-analysis due to 100% mortality in both study arms. DOI: http://dx.doi.org/10.7554/eLife.17850.006

Figure 2—figure supplement 2.. Forest plot summarizing relationship of mesenchymal stromal cell (MSC) dose on mortality in preclinical models of sepsis and endotoxemia.

Point estimates (odds ratio) and 95% confidence intervals (CI) are depicted for individual studies; size of point estimate depicts relative contribution to pooled effect. A pooled meta-analytic summary (random effects model) of overall effect is depicted by the diamond at the bottom of each subgroup (vertical points represent odds ratio point estimate and horizontal points represent 95% CIs). Heterogeneity is represented with the I² statistic. Data from Pedrazza et al 2014 was included in total counts but not included in meta-analysis due to 100% mortality in both study arms. DOI: http://dx.doi.org/10.7554/eLife.17850.007

Figure 2—figure supplement 3.. Forest plot summarizing relationship of mesenchymal stromal cell (MSC) therapy timing of administration on mortality in preclinical models of sepsis and endotoxemia.

Point estimates (odds ratio) and 95% confidence intervals (CI) are depicted for individual studies; size of point estimate depicts relative contribution to pooled effect. A pooled meta-analytic summary (random effects model) of overall effect is depicted by the diamond at the bottom of each subgroup (vertical points represent odds ratio point estimate and horizontal points represent 95% CIs). Heterogeneity is represented with the I² statistic. Data from Pedrazza et al 2014 was included in total counts but not included in meta-analysis due to 100% mortality in both study arms. DOI: http://dx.doi.org/10.7554/eLife.17850.008

Figure 2—figure supplement 4.. Forest plot summarizing relationship of mesenchymal stromal cell (MSC) administration route (intravenous vs intraperitoneal) on mortality in preclinical models of sepsis and endotoxemia.

Point estimates (odds ratio) and 95% confidence intervals (CI) are depicted for individual studies; size of point estimate depicts relative contribution to pooled effect. A pooled meta-analytic summary (random effects model) of overall effect is depicted by the diamond at the bottom of each subgroup (vertical points represent odds ratio point estimate and horizontal points represent 95% CIs). Heterogeneity is represented with the I² statistic. Data from Pedrazza et al 2014 was included in total counts but not included in meta-analysis due to 100% mortality in both study arms. DOI: http://dx.doi.org/10.7554/eLife.17850.009

Figure 2—figure supplement 5.. Forest plot summarizing relationship of mesenchymal stromal cell (MSC) tissue source (adipose vs bone marrow vs umbilical cord tissue) on mortality in preclinical models of sepsis and endotoxemia.

Point estimates (odds ratio) and 95% confidence intervals (CI) are depicted for individual studies; size of point estimate depicts relative contribution to pooled effect. A pooled meta-analytic summary (random effects model) of overall effect is depicted by the diamond at the bottom of each subgroup (vertical points represent odds ratio point estimate and horizontal points represent 95% CIs). Heterogeneity is represented with the I² statistic. Data from Pedrazza et al 2014 was included in total counts but not included in meta-analysis due to 100% mortality in both study arms. DOI: http://dx.doi.org/10.7554/eLife.17850.010

Figure 2—figure supplement 6.. Forest plot summarizing relationship of animal species (rat vs mouse) on mortality in preclinical models of sepsis and endotoxemia treated with mesenchymal stromal cells (MSCs).

Point estimates (odds ratio) and 95% confidence intervals (CI) are depicted for individual studies; size of point estimate depicts relative contribution to pooled effect. A pooled meta-analytic summary (random effects model) of overall effect is depicted by the diamond at the bottom of each subgroup (vertical points represent odds ratio point estimate and horizontal points represent 95% CIs). Heterogeneity is represented with the I² statistic. Data from Pedrazza et al 2014 was included in total counts but not included in meta-analysis due to 100% mortality in both study arms. DOI: http://dx.doi.org/10.7554/eLife.17850.011

Figure 2—figure supplement 7.. Forest plot summarizing relationship of animal sex (male vs female vs unreported) on mortality in preclinical models of sepsis and endotoxemia treated with mesenchymal stromal cells (MSCs).

Point estimates (odds ratio) and 95% confidence intervals (CI) are depicted for individual studies; size of point estimate depicts relative contribution to pooled effect. A pooled meta-analytic summary (random effects model) of overall effect is depicted by the diamond at the bottom of each subgroup (vertical points represent odds ratio point estimate and horizontal points represent 95% CIs). Heterogeneity is represented with the I² statistic. Data from Pedrazza et al 2014 was included in total counts but not included in meta-analysis due to 100% mortality in both study arms. DOI: http://dx.doi.org/10.7554/eLife.17850.012

Figure 2—figure supplement 8.. Forest plot summarizing relationship of preclinical models of sepsis and endotoxemia (cecal ligation and puncture vs live bacteria administration vs bacterial product such as lipopolysaccharide) on mortality following treatment with mesenchymal stromal cells (MSCs).

Point estimates (odds ratio) and 95% confidence intervals (CI) are depicted for individual studies; size of point estimate depicts relative contribution to pooled effect. A pooled meta-analytic summary (random effects model) of overall effect is depicted by the diamond at the bottom of each subgroup (vertical points represent odds ratio point estimate and horizontal points represent 95% CIs). Heterogeneity is represented with the I² statistic. Data from Pedrazza et al 2014 was included in total counts but not included in meta-analysis due to 100% mortality in both study arms. DOI: http://dx.doi.org/10.7554/eLife.17850.013

Figure 2—figure supplement 9.. Forest plot summarizing relationship of resuscitation (fluids +/- antibiotics vs no resuscitation) on mortality in preclinical models of sepsis and endotoxemia treated with mesenchymal stromal cells (MSCs).

Point estimates (odds ratio) and 95% confidence intervals (CI) are depicted for individual studies; size of point estimate depicts relative contribution to pooled effect. A pooled meta-analytic summary (random effects model) of overall effect is depicted by the diamond at the bottom of each subgroup (vertical points represent odds ratio point estimate and horizontal points represent 95% CIs). Heterogeneity is represented with the I² statistic. Data from Pedrazza et al 2014 was included in total counts but not included in meta-analysis due to 100% mortality in both study arms. DOI: http://dx.doi.org/10.7554/eLife.17850.014

Figure 2—figure supplement 10.. Forest plot summarizing relationship of comparison (control) treatment on mortality in preclinical models of sepsis and endotoxemia treated with mesenchymal stromal cells (MSCs).

Point estimates (odds ratio) and 95% confidence intervals (CI) are depicted for individual studies; size of point estimate depicts relative contribution to pooled effect. A pooled meta-analytic summary (random effects model) of overall effect is depicted by the diamond at the bottom of each subgroup (vertical points represent odds ratio point estimate and horizontal points represent 95% CIs). Heterogeneity is represented with the I² statistic. Data from Pedrazza et al 2014 was included in total counts but not included in meta-analysis due to 100% mortality in both study arms. DOI: http://dx.doi.org/10.7554/eLife.17850.015

Figure 2—figure supplement 11.. Forest plot summarizing relationship of adherence to elements of construct validity on mortality in preclinical models of sepsis and endotoxemia treated with mesenchymal stromal cells (MSCs).

Subgroups are studies that adhered to a majority of elements suggested to increase construct validity (≥5 of 8; see text for details of elements) vs those that did not adhere to majority. Point estimates (odds ratio) and 95% confidence intervals (CI) are depicted for individual studies; size of point estimate depicts relative contribution to pooled effect. A pooled meta-analytic summary (random effects model) of overall effect is depicted by the diamond at the bottom of each subgroup (vertical points represent odds ratio point estimate and horizontal points represent 95% CIs). Heterogeneity is represented with the I² statistic. Data from Pedrazza et al 2014 was included in total counts but not included in meta-analysis due to 100% mortality in both study arms. DOI: http://dx.doi.org/10.7554/eLife.17850.016

Figure 3.. Forest plot summarizing relationship of mesenchymal stromal cell (MSC) therapy on mortality over time in preclinical models of sepsis and endotoxemia (outcome windows: ≤2 days, >2 to ≤ 4 days, > 4 days).

Point estimates (odds ratio) and 95% confidence intervals (CI) are depicted for individual studies; size of point estimate depicts relative contribution to pooled effect. A pooled meta-analytic summary (random effects model) of overall effect of MSC therapy on mortality is depicted by the diamond at the bottom of each time interval (vertical points represent odds ratio point estimate and horizontal points represent 95% CIs). Heterogeneity is represented with the I² statistic. Data from Pedrazza et al. (2014) was included in total counts but not included in meta-analysis due to 100% mortality in both study arms. DOI: http://dx.doi.org/10.7554/eLife.17850.017

Figure 4.. Funnel plot to detect publication bias.

Trim and fill analysis was performed on overall mortality. Open circles denote original data, black circles denote ‘filled’ studies. Open diamond denotes original pooled effect size (log odds ratio) and 95% confidence interval. Filled diamond represents adjusted effect size and 95% confidence interval. DOI: http://dx.doi.org/10.7554/eLife.17850.021