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.

Combined Bone Marrow-Derived Mesenchymal Stromal Cell Therapy and One-Way Endobronchial Valve Placement in Patients with Pulmonary Emphysema: A Phase I Clinical Trial

“…Systemic administration of autologous and allogeneic MSCs has been uniformly demonstrated as safe in a wide range of diseases, without infusion‐related toxicity or significant adverse effects over at least 5 years after administration, as shown in recent meta‐analyses 28. Preclinical studies have also demonstrated the safety of intrabronchial MSC administration, and a small number of trials support the clinical safety of this approach 27.…”

The Devil Is in the Details: Incomplete Reporting in Preclinical Animal Research

“…We utilized 47 English language studies there were previously identified in a systematic review of acute lung injury and MSCs [15]. A detailed protocol for the systematic was pre-registered [29] and published [16] prior to conducting the research.…”

“…A detailed protocol for the systematic was pre-registered [29] and published [16] prior to conducting the research. A list of the included studies is included in S1 Table and general characteristics of the included studies are published in our systematic review [15]. …”

“…Here we sought to determine the scope of reporting in greater detail by focusing on a particular preclinical animal model (acute lung injury) and treatment (MSCs) as part of a systematic review [15]. Our search strategy resulted in 5,391 total records which after screening left 47 English language articles that met our prespecified criteria from our protocol [16] (see methods and S1 Fig, S1 Table).…”

Developmental pathways in lung regeneration

“…Other cellular options such as mesenchymal stromal/stem cells, have not demonstrated efficacy beyond a small anti-inflammatory paracrine affect (Stabler, Lecht et al 2015, Ikonomou, Freishtat et al 2016, McIntyre, Moher et al 2016). In contrast, the use of iPSCs to generate lung cell lineages for replacement of cells due to acute injury or disease related loss, could eventually be used for regenerative purposes.…”