Abstract
BackgroundHuman mesenchymal stem/stromal cells (hMSCs) represent a promising therapeutic strategy for ventilator-induced lung injury (VILI) and acute respiratory distress syndrome. Translational challenges include restoring hMSC efficacy following cryopreservation, developing effective xenogeneic-free (XF) hMSCs and establishing true therapeutic potential at a clinically relevant time point of administration. We wished to determine whether cytokine pre-activation of cryopreserved, bone marrow-derived XF-hMSCs would enhance their capacity to facilitate injury resolution following VILI and elucidate mechanisms of action.MethodsInitially, in vitro studies examined the potential for the secretome from cytokine pre-activated XF-hMSCs to attenuate pulmonary epithelial injury induced by cyclic mechanical stretch. Later, anaesthetised rats underwent VILI and, 6 h following injury, were randomized to receive 1 × 107 XF-hMSC/kg that were (i) naive fresh, (ii) naive cryopreserved, (iii) cytokine pre-activated fresh or (iv) cytokine pre-activated cryopreserved, while control animals received (v) vehicle. The extent of injury resolution was measured at 24 h after injury. Finally, the role of keratinocyte growth factor (KGF) in mediating the effect of pre-activated XF-hMSCs was determined in a pulmonary epithelial wound repair model.ResultsPre-activation enhanced the capacity of the XF-hMSC secretome to decrease stretch-induced pulmonary epithelial inflammation and injury. Both pre-activated fresh and cryopreserved XF-hMSCs enhanced resolution of injury following VILI, restoring oxygenation, improving lung compliance, reducing lung leak and improving resolution of lung structural injury. Finally, the secretome of pre-activated XF-hMSCs enhanced epithelial wound repair, in part via a KGF-dependent mechanism.ConclusionsCytokine pre-activation enhanced the capacity of cryopreserved, XF-hMSCs to promote injury resolution following VILI, potentially via a KGF-dependent mechanism.
Highlights
Human mesenchymal stem/stromal cells represent a promising therapeutic strategy for ventilator-induced lung injury (VILI) and acute respiratory distress syndrome
Cytokine pre-activation enhanced the capacity of cryopreserved, XFhMSCs to promote injury resolution following VILI, potentially via a keratinocyte growth factor (KGF)-dependent mechanism
In vitro assessments Pulmonary epithelial cell stretch-induced injury Cyclic mechanical stretch-induced NF-κB activation was attenuated by both foetal bovine serum (FBS)- and XF-cultured Human mesenchymal stem/stromal cells (hMSCs)-conditioned medium (CM) as compared to the control (MEM-α) group (Fig. 1a)
Summary
Human mesenchymal stem/stromal cells (hMSCs) represent a promising therapeutic strategy for ventilator-induced lung injury (VILI) and acute respiratory distress syndrome. Translational challenges include restoring hMSC efficacy following cryopreservation, developing effective xenogeneic-free (XF) hMSCs and establishing true therapeutic potential at a clinically relevant time point of administration. Mechanical ventilation is a potentially life-saving manoeuvre in patients with acute respiratory distress syndrome (ARDS) [1, 2], but it can exacerbate lung damage—this is termed ventilation-induced lung injury (VILI) [3]. Mesenchymal stem/stromal cells (MSCs) demonstrate beneficial effects in diverse pre-clinical lung injury models including pulmonary [4,5,6] and abdominal sepsis [7,8,9], bleomycin-induced acute lung injury [10] and fibrosis [11, 12]. Demonstrating true ‘therapeutic’ potential of MSC therapies, i.e. showing efficacy at later points (delayed administration) in the injury and/or repair process, is necessary to better mimic the clinical scenario
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