Mesenchymal stromal cell‐derived small extracellular vesicles restore lung architecture and improve exercise capacity in a model of neonatal hyperoxia‐induced lung injury

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.

A Review of Placenta and Umbilical Cord-Derived Stem Cells and the Immunomodulatory Basis of Their Therapeutic Potential in Bronchopulmonary Dysplasia

“…Similar therapeutic effects were observed in hyperoxia-induced neonatal lung injury in mice treated both with early and late EVs interventions ( 129 ). EVs might even potentially reverse the cardiorespiratory complications in children with developed BPD ( 129 ).…”

“…Similar therapeutic effects were observed in hyperoxiainduced neonatal lung injury in mice treated both with early and late EVs interventions (129). EVs might even potentially reverse the cardiorespiratory complications in children with developed BPD (129). In addition, Tan et al (130) reported that the release of EVs from hAECs administered intranasally exerted similar beneficial effects to MSCs with significant reduction in lung inflammation, improvement in tissue-to-airspace ratio and reduction in fibrosis in bleomycin-challenged aged mice (130).…”

“…In addition, Tan et al ( 130 ) reported that the release of EVs from hAECs administered intranasally exerted similar beneficial effects to MSCs with significant reduction in lung inflammation, improvement in tissue-to-airspace ratio and reduction in fibrosis in bleomycin-challenged aged mice ( 130 ). Willis et al ( 129 ) and Bonadies et al ( 131 ) suggested that MSCs and EVs are two most revolutionary treatments for BPD, not only effective in the prevention of BPD but also may potentially reverse the complications in children diagnosed with BPD ( 129 , 131 ).…”

“…It is suggested that UC-MSCs may act via a paracrine effect. Purified exosomes from various sources of MSCs including Wharton's jelly-derived MSCs were also reported to restore lung architecture and improve lung development and function in hyperoxia-induced BPD animal models ( 129 ).…”

MSC Based Therapies to Prevent or Treat BPD—A Narrative Review on Advances and Ongoing Challenges

“…Application during the acute phase of injury but even after 14 days of hyperoxic exposure proved efficient to attenuate or completely revert the deleterious consequences for lung structure and functional properties [ 29 , 45 , 60 , 61 , 68 , 96 , 97 , 98 , 99 , 100 , 101 ]. Detailed structural and functional analyses demonstrated benefits not only for pulmonary hypertension but for peripheral vascular remodeling and for the pool of bronchioloalveolar stem cells as well [ 60 , 68 , 96 , 97 , 100 ]. Dissection of the inflammatory response revealed a reduced influx of neutrophils, an M1 to M2 shift in macrophages, suppression of pro-inflammatory cytokines and augmentation of anti-inflammatory cytokines and growth factors [ 53 , 97 , 99 ].…”