MSC Microvesicles for the Treatment of Lung Disease: A New Paradigm for Cell-Free Therapy

Abstract

Significance: Bronchopulmonary dysplasia (BPD), also known as chronic lung disease of infancy, is a major complication of preterm birth that, despite improvements in neonatal respiratory support and perinatal care, remains an important cause of morbidity and mortality, often with severe adverse neurodevelopmental sequelae. Even with major advances in our understanding of the pathogenesis of this disease, BPD remains essentially without adequate treatment. Recent Advances: Cell-based therapies arose as a promising treatment for acute and chronic lung injury in many experimental models of disease. Currently, more than 3000 human clinical trials employing cell therapy for the treatment of diverse diseases, including cardiac, neurologic, immune, and respiratory conditions, are ongoing or completed. Among the treatments, mesenchymal stem cells (MSCs) are the most studied and have been extensively tested in experimental models of BPD, pulmonary hypertension, pulmonary fibrosis, and acute lung injury. Critical Issues: Despite the promising potential, MSC therapy for human lung disease still remains at an experimental stage and optimal transplantation conditions need to be determined. Although the mechanism of MSC action can be manifold, accumulating evidence suggests a predominant paracrine, immunomodulatory, and cytoprotective effect. Future Directions: The current review summarizes the effect of MSC treatment in models of lung injury, including BPD, and focuses on the MSC secretome and, specifically, MSC-derived microvesicles as potential key mediators of therapeutic action that can be the focus of future therapies. Antioxid. Redox Signal. 21, 1905Signal. 21, -1915

Strategies to enhance paracrine potency of transplanted mesenchymal stem cells in intractable neonatal disorders

“…Recently, in addition to the cytokines and other secreted molecules mentioned above, MSC derived-extracellular vesicles (EVs) or exosomes (28,40,(61)(62)(63) were shown to be key mediators of MSC therapeutic action (62)(63)(64). EVs derived from MSCs show therapeutic effects on various tissue injury in preclinical animal models by modulating immune response (65), ameliorating oxidative stress (66), and decreasing apoptosis (67), which is similar to what is achieved using the originating MSCs themselves.…”

Mesenchymal stem cells: mechanisms of potential therapeutic benefit in ARDS and sepsis

“…90 As with MSC therapy, a push for expedited clinical trials will need to be balanced with a focus on basic and translational research to improve the understanding of the in-vitro and in-vivo behaviour of cell-free therapies. Attention will need to be given to the full identifi cation and classifi cation of the bioactive molecules secreted by MSCs, determination of how cell-free therapies diff er in both safety and effi cacy (conditioned media vs isolated bioactive factors vs exosomes), and tests of whether potential therapies should be given as single drugs or in combination.…”

Murine model: maternal administration of stem cells for prevention of prematurity

“…60,61 Because of their properties, MSC treatment has been tested in clinical trials of diseases and animal studies. 62-66 In clinical trials, when transplanted to recipients, MSCs are used to treat graft-vs-host disease.…”