Microvesicles Derived From Human Mesenchymal Stem Cells Restore Alveolar Fluid Clearance in Human Lungs Rejected for Transplantation

Abstract

The need to increase the donor pool for lung transplantation is a major public health issue. We previously found that administration of mesenchymal stem cells “rehabilitated” marginal donor lungs rejected for transplantation using ex vivo lung perfusion. However, the use of stem cells has some inherent limitation such as the potential for tumor formation. In the current study, we hypothesized that microvesicles, small anuclear membrane fragments constitutively released from mesenchymal stem cells, may be a good alternative to using stem cells. Using our well established ex vivo lung perfusion model, microvesicles derived from human mesenchymal stem cells increased alveolar fluid clearance (i.e. ability to absorb pulmonary edema fluid) in a dose-dependent manner, decreased lung weight gain following perfusion and ventilation, and improved airway and hemodynamic parameters compared to perfusion alone. Microvesicles derived from normal human lung fibroblasts as a control had no effect. Co-administration of microvesicles with anti-CD44 antibody attenuated these effects, suggesting a key role of the CD44 receptor in the internalization of the microvesicles into the injured host cell and its effect. In summary, microvesicles derived from human mesenchymal stem cells were as effective as the parent mesenchymal stem cells in rehabilitating marginal donor human lungs.

Mesenchymal Stromal Cells Modulate Macrophages in Clinically Relevant Lung Injury Models by Extracellular Vesicle Mitochondrial Transfer

“…Litvack and colleagues also showed that, although not true AMs, stem cell-derived, alveolar-like macrophages improved bacterial and neutrophil clearance in another model of lung injury (49), but further study is required to determine the safety and feasibility of these treatment modalities. Moreover, these data contribute to the growing body of literature that suggests the potential of MSC-derived EVs as a therapy in place of MSCs (25)(26)(27). Although there have been no reports of MSC-induced neoplasia to date, EVs cannot themselves transform to form tumors, reducing the potential risk associated with cell-based therapy.…”

“…Additionally, the capacity of MSCs to induce polarization toward M2-type monocytes/macrophages, identified by CD206 expression, may serve as a biomarker for MSC efficacy in clinical samples. EVs have emerged as a major contributor to the therapeutic effects of MSCs in lung injury, capable of recapitulating many of the effects of the whole-cell therapy (25)(26)(27). CD44 expression on MSC-derived EVs was shown to be necessary for their uptake and therapeutic effect on target cells (27,50).…”

“…MSC-derived EVs may contain a diverse cargo, including proteins, mRNAs, microRNAs (miRNAs), and mitochondria, the functional effects of which remain largely unknown (9,(23)(24)(25). MSC-derived EVs alone are capable of recapitulating many of the beneficial effects of MSC whole-cell therapy (25)(26)(27)(28). Phinney and colleagues observed the transfer of MSC mitochondria and miRNAs via EVs to human macrophages in a model of silicosis and found that mitochondria enhanced macrophage bioenergetics, whereas miRNAs suppressed Toll-like receptor signaling (24).…”

Mesenchymal stem cell derived secretome and extracellular vesicles for acute lung injury and other inflammatory lung diseases

“…To date, only a few groups have studied the therapeutic effects of MSC vesicles in acute inflammatory lung diseases such as ALI[16, 103–105], pulmonary artery hypertension (PAH)[106, 107] and asthma[108]. Although the mechanisms of action have not been fully defined, these groups have demonstrated that MSC vesicles are as potent as their parent stem cells as therapy (Figure 4).…”

“…In an ex vivo human lung perfusion model of I/R seen in lung transplantation[15], Gennai et al[105] found that MSC MVs increased alveolar fluid clearance (e.g., ability to absorb pulmonary edema fluid) in a dose-dependent manner, decreased lung weight gain following perfusion and ventilation, and improved airway and hemodynamic parameters compared to perfusion alone. Co-administration of MVs with anti-CD44 antibody attenuated these effects, suggesting a key role of the CD44 receptor in the internalization of the MVs into the injured host cell and its effect.…”