ABSTRACT

Early administration of mesenchymal stromal cell (MSC)-derived small extracellular vesicles (MEx) has shown considerable promise in experimental models of bronchopulmonary dysplasia (BPD). However, the ability of MEx to reverse the long-term pulmonary complications associated with established BPD remains unknown. In this study, MEx were isolated from media conditioned by human Wharton’s Jelly-derived MSC cultures. Newborn mice (FVB strain) were exposed to hyperoxia (HYRX (75% O2)) before returning to room air at postnatal day 14 (PN14). Following prolonged HYRX-exposure, animals received a single MEx dose at PN18 or serial MEx treatments at PN18-39 (“late” intervention). This group was compared to animals that received an early single MEx dose at PN4 (“early” intervention). Animals were harvested at PN28 or 60 for assessment of pulmonary parameters. We found that early and late MEx interventions effectively ameliorated core features of HYRX-induced neonatal lung injury, improving alveolar simplification, pulmonary fibrosis, vascular remodelling and blood vessel loss. Exercise capacity testing and assessment of pulmonary hypertension (PH) showed functional improvements following both early and late MEx interventions. In conclusion, delivery of MEx following prolonged HYRX-exposure improves core features of experimental BPD, restoring lung architecture, decreasing pulmonary fibrosis and vascular muscularization, ameliorating PH and improving exercise capacity. Taken together, delivery of MEx may not only be effective in the immediate neonatal period to prevent the development of BPD but may provide beneficial effects for the management and potentially the reversal of cardiorespiratory complications in infants and children with established BPD.

摘要

间充质基质细胞 (MSC) 衍生的小细胞外囊泡 (MEx) 的早期给药在支气管肺发育不良 (BPD) 的实验模型中显示出相当大的前景。然而，MEx 逆转与既定 BPD 相关的长期肺部并发症的能力仍然未知。在这项研究中，MEx 是从人类沃顿氏果冻衍生的 MSC 培养物条件化的培养基中分离出来的。新生小鼠（FVB 品系）在出生后第 14 天（PN14）返回室内空气之前暴露于高氧环境（HYRX（75% O2））。长时间暴露于 HYRX 后，动物在 PN18 接受单次 MEx 剂量或在 PN18-39 接受连续 MEx 治疗（“后期”干预）。将该组与在 PN4 接受早期单次 MEx 剂量（“早期”干预）的动物进行比较。在 PN28 或 60 时收获动物用于评估肺参数。我们发现早期和晚期 MEx 干预有效地改善了 HYRX 诱导的新生儿肺损伤的核心特征，改善了肺泡简化、肺纤维化、血管重塑和血管丢失。运动能力测试和肺动脉高压 (PH) 评估显示早期和晚期 MEx 干预后功能改善。总之，长时间暴露于 HYRX 后递送 MEx 可改善实验性 BPD 的核心特征，恢复肺结构，减少肺纤维化和血管肌肉化，改善 PH 并提高运动能力。综合起来，