Program in Molecular Medicine; Diabetes Center of Excellence; Graduate School of Biomedical Sciences
Cell and Developmental Biology | Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Hemic and Immune Systems | Immunity | Immunopathology | Pediatrics | Respiratory Tract Diseases
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.
extracellular vesicle (EV), hyperoxia (oxygen), mesechymal stromal cell, neonatal immune system, thymus
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Copyright © 2021 Reis, Willis, Fernandez-Gonzalez, Yeung, Taglauer, Magaletta, Parsons, Derr, Liu, Maehr, Kourembanas and Mitsialis. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
DOI of Published Version
Reis M, Willis GR, Fernandez-Gonzalez A, Yeung V, Taglauer E, Magaletta M, Parsons T, Derr A, Liu X, Maehr R, Kourembanas S, Mitsialis SA. Mesenchymal Stromal Cell-Derived Extracellular Vesicles Restore Thymic Architecture and T Cell Function Disrupted by Neonatal Hyperoxia. Front Immunol. 2021 Apr 15;12:640595. doi: 10.3389/fimmu.2021.640595. PMID: 33936055; PMCID: PMC8082426. Link to article on publisher's site
Frontiers in immunology
Reis M, Willis GR, Fernandez-Gonzalez A, Yeung V, Taglauer E, Magaletta M, Parsons TJ, Derr AG, Liu X, Maehr R, Kourembanas S, Mitsialis SA. (2021). Mesenchymal Stromal Cell-Derived Extracellular Vesicles Restore Thymic Architecture and T Cell Function Disrupted by Neonatal Hyperoxia. Open Access Publications by UMass Chan Authors. https://doi.org/10.3389/fimmu.2021.640595. Retrieved from https://escholarship.umassmed.edu/oapubs/4682
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Cell and Developmental Biology Commons, Congenital, Hereditary, and Neonatal Diseases and Abnormalities Commons, Hemic and Immune Systems Commons, Immunity Commons, Immunopathology Commons, Pediatrics Commons, Respiratory Tract Diseases Commons