Mesenchymal Stromal Cell-Derived Extracellular Vesicles Restore Thymic Architecture and T Cell Function Disrupted by Neonatal Hyperoxia

Abstract

Treating premature infants with high oxygen is a routine intervention in the context of neonatal intensive care. Unfortunately, the increase in survival rates is associated with various detrimental sequalae of hyperoxia exposure, most notably bronchopulmonary dysplasia (BPD), a disease of disrupted lung development. The effects of high oxygen exposure on other developing organs of the infant, as well as the possible impact such disrupted development may have on later life remain poorly understood. Using a neonatal mouse model to investigate the effects of hyperoxia on the immature immune system we observed a dramatic involution of the thymic medulla, and this lesion was associated with disrupted FoxP3+ regulatory T cell generation and T cell autoreactivity. Significantly, administration of mesenchymal stromal cell-derived extracellular vesicles (MEx) restored thymic medullary architecture and physiological thymocyte profiles. Using single cell transcriptomics, we further demonstrated preferential impact of MEx treatment on the thymic medullary antigen presentation axis, as evidenced by enrichment of antigen presentation and antioxidative-stress related genes in dendritic cells (DCs) and medullary epithelial cells (mTECs). Our study demonstrates that MEx treatment represents a promising restorative therapeutic approach for oxygen-induced thymic injury, thus promoting normal development of both central tolerance and adaptive immunity.

The Lineage Differentiation and Dynamic Heterogeneity of Thymic Epithelial Cells During Thymus Organogenesis

“…Mesenchymal fibroblast cells were demonstrated to be required for formation of thymic microenvironment by producing retinoic acid ( 92 ). Mesenchymal stromal cells or their extracellular vesicles showed great potential in promoting thymic epithelial cell expansion and differentiation ( 93 , 94 ). To further investigate the factors mediating the development of TECs by mesenchymal fibroblast, we systematically investigated the ligand–receptor interactions specifically expressed across these cell types (see Materials and Methods ).…”

Extracellular Vesicles Secreted by Corneal Myofibroblasts Promote Corneal Epithelial Cell Migration

“…All EV samples prepared and analyzed as previously published [ 20 , 32 , 34 ]. All EV samples were diluted in PBS to a final volume of 1 mL.…”

“…To date, our understanding of stromal cells, such as adipocytes, fibrocytes, fibroblasts, and mesenchymal stem cells (MSCs), along with their secreted EVs, has been reported in studies that mediate disease-exacerbating changes in asthma [ 17 ], cancer [ 18 , 19 , 20 , 21 , 22 ], fibrosis [ 23 , 24 , 25 ], and cardiovascular diseases [ 26 , 27 , 28 ], but also show the therapeutic action of MSC-EVs by targeting different tissues, including the lungs, placenta, and thymus [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ]. By focusing on the cornea, studies have investigated how corneal MSC-EVs can improve corneal epithelial wound healing, reduce corneal epithelial defects, and promote scarless stromal recovery post-corneal injury in vivo [ 38 , 39 , 40 , 41 ].…”

Mesenchymal Stem Cell-Derived Extracellular Vesicles for the Treatment of Bronchopulmonary Dysplasia

“…In vitro and in vivo studies revealed that MSC-EVs promoted an immunosuppressive in bone marrow-derived myeloid cells phenotype. A study ( 55 ) demonstrated that MSC-EVs treatment represents a promising restorative therapeutic approach for oxygen-induced thymic injury, thus promoting normal development of both central tolerance and adaptive immunity.…”