DataSheet_1_Mesenchymal Stromal Cell-Derived Extracellular Vesicles Restore Thymic Architecture and T Cell Function Disrupted by Neonatal Hyperoxia.docx

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.

在新生儿重症监护的背景下，对早产儿使用高浓度氧气是一种常规干预措施。遗憾的是，生存率的提升伴随着高氧暴露所引起的诸多不利后果，其中最显著的是支气管肺发育不良（BPD），一种肺部发育失调的疾病。高氧暴露对婴儿其他发育中的器官的影响，以及这种发育失调可能对后期生活造成的潜在影响，目前尚缺乏深入了解。通过利用新生儿小鼠模型研究高氧对未成熟免疫系统的影响，我们观察到胸腺髓质的显著退化，这一病变与FoxP3+调节性T细胞的生成障碍和T细胞自身反应性增加有关。值得注意的是，间充质干细胞来源的细胞外囊泡（MEx）的处理能够恢复胸腺髓质的解剖结构和生理性胸腺细胞谱系。通过单细胞转录组学技术，我们进一步证明了MEx治疗对胸腺髓质抗原呈递轴的偏好性影响，这一发现体现在树突状细胞（DCs）和髓质上皮细胞（mTECs）中抗原呈递和抗氧化应激相关基因的富集。本研究表明，MEx治疗是一种具有前景的修复性治疗方案，适用于由氧气引起的胸腺损伤，从而促进中枢耐受性和适应性免疫的正常发育。