Modulation of thymic architecture and T cell function by Mesenchymal stromal cell extracellular vesicles in a model of neonatal hyperoxia

Abstract

Abstract Therapies based on mesenchymal stem/stromal cell extracellular vesicles (MEx) have shown promise in experimental models of bronchopulmonary dysplasia (BPD), a disease of disrupted lung development that can result from neonatal exposure to hyperoxia. The effects of oxygen exposure on other developing organs in the neonatal period remain poorly understood and whether MEx treatment may modify these responses is not known. Our research aimed at understanding the effects of neonatal exposure to hyperoxia and the immunomodulatory properties of MEx on thymic architecture and T cell development. Using a mouse model of neonatal hyperoxia, we showed that, in addition to lung injury resulting in BPD, there was involution of the thymic medulla with altered T cell function. Administration of a single dose of MEx resulted in preservation of thymic architecture, and restoration of normal thymic function through modulation of the thymic medullary antigen presentation network and T cell phenotypes. Consequently, MEx reinstated the mechanisms of thymic-driven central tolerance that are perturbed upon hyperoxia exposure, as demonstrated by increased FoxP3+ regulatory T cell generation and decreased T cell autoreactivity. Overall, our study demonstrates that MEx represent a promising cell-free therapeutic option to restore thymic architecture and ensure the development of central tolerance by preventing thymic injury associated with neonatal hyperoxia exposure.