Abstract
Mesenchymal stem/stromal cells (MSCs) have demonstrated efficacy in pre-clinical models of inflammation and tissue injury, including in models of lung injury and infection. Rolling, adhesion and transmigration of MSCs appears to play a role during MSC kinetics in the systemic vasculature. However, a large proportion of MSCs become entrapped within the lungs after intravenous administration, while the initial kinetics and the site of arrest of MSCs in the pulmonary vasculature are unknown. We examined the kinetics of intravascularly administered MSCs in the pulmonary vasculature using a microfluidic system in vitro and intra-vital microscopy of intact mouse lung. In vitro, MSCs bound to endothelium under static conditions but not under laminar flow. VCAM-1 antibodies did not affect MSC binding. Intravital microscopy demonstrated MSC arrest at pulmonary micro-vessel bifurcations due to size obstruction. Retention of MSCs in the pulmonary microvasculature was increased in Escherichia coli-infected animals. Trapped MSCs deformed over time and appeared to release microvesicles. Labelled MSCs retained therapeutic efficacy against pneumonia. Our results suggest that MSCs are physically obstructed in pulmonary vasculature and do not display properties of rolling/adhesion, while retention of MSCs in the infected lung may require receptor interaction.
Highlights
Mesenchymal stem/stromal cells (MSCs) have demonstrated efficacy in pre-clinical models of inflammation and tissue injury, including in models of lung injury and infection
The current studies provide important insights into initial kinetics and site of arrest of systemically administered MSCs within the pulmonary microcirculation, and mechanisms mediating this interaction between the MSC and the pulmonary endothelium
The demonstration that lung injury increases the retention of physically entrapped MSCs in the pulmonary microcirculation, and that entrapped MSCs release microvesicles may provide targets to enhance the efficacy of MSC therapies in the injured lung
Summary
Mesenchymal stem/stromal cells (MSCs) have demonstrated efficacy in pre-clinical models of inflammation and tissue injury, including in models of lung injury and infection. Mesenchymal stem/stromal cells (MSCs) have demonstrated efficacy in pre-clinical models of inflammation and tissue injury, including in models of lung injury and infection[1,2,3,4], and in systemic s epsis[5,6,7]. As described by Ince and c olleagues[28] the pathogenic effects of sepsis in the endothelium involves glycocalyx destruction leading to integrin and selectin exposure, increasing trapping and transmigration of leukocytes, which could potentially impact MSC adhesion and retention in the lung during pneumonia. There is emerging evidence that MSCs can extravasate from the systemic vasculature in a murine model of dermal inflammation[14], and from the pulmonary vasculature into the alveolus during Escherichia coli pneumonia[4]
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