Efficacy of Mesenchymal Stromal Cell Therapy for Acute Lung Injury in Preclinical Animal Models: A Systematic Review

Abstract

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.

Fig 1. PRISMA flow diagram.

Fig 2. Forest plot of mesenchymal stem cellson the odds of mortality in preclinical models of acute lung injury.

Letters indicate two separate mortality experiments within one publication.

Fig 3. Subgroup analyses of mesenchymal stem cellson the odds of mortality in preclinical models of acute lung injury.

Fig 3A: Forest plot of mesenchymal stem cells on the odds of mortality at a priori determined time points. Fig 3B: Forest plot of mesenchymal stem cells on the odds of mortality according to animal species, gender and experimental model of acute lung injury. Fig 3C: Forest plot of mesenchymal stem cells on the odds of mortality according to MSC origin, source, preparation, and route of administration, as well as comparator control groups. Subgroup analyses conducted to examine the robustness of the treatment effect according to the clinical relevance of the ALI model (timing of MSC administration in relation to ALI induction and resuscitation of the animals) (Fig 3D) indicated a reduction in the odds of death regardless of the timing of administration of the cells, although the protective effect of MSCs appeared less the longer the delay in treatment initiation. There were no significant differences in the treatment effect of MSCs with more clinically relevant animal models (e.g. use of antibiotics, resuscitation fluid, or the combination of resuscitation fluid and antibiotics). Analyses conducted according to selective outcome reporting and incomplete outcome reporting did not reveal substantial differences in the estimate of effect (Fig 3E). Fig 3D: Forest plot of mesenchymal stem cells on the odds of mortality according to timing of MSC administration and method of resuscitation. Fig 3E: Forest plot of mesenchymal stem cells on the odds of mortality according to domains of the Cochrane Risk of Bias.

Fig 4. Funnel plot of standard error by log odds ratio for overall mortality indicates the possibility of publication bias.