Published online Jul 26, 2022. doi: 10.4252/wjsc.v14.i7.556
Peer-review started: March 30, 2022
First decision: April 25, 2022
Revised: May 4, 2022
Accepted: June 20, 2022
Article in press: June 20, 2022
Published online: July 26, 2022
Processing time: 117 Days and 20.6 Hours
Increasing evidence has suggested that bronchopulmonary dysplasia (BPD) is not merely a lung disease, but a systemic condition with short-term and long-term multiple organ implications. Exposure to hyperoxia causes oxidative stress and contributes to the pathogenesis of these recognized implications, including respiratory morbidity, cardiac dysfunction, and impairments in renal development. Mesenchymal stem cells (MSCs) are multipotent stromal cells that have immunomodulatory, anti-inflammatory, and low immunogenicity properties and have shown great potential for the management of a range of different neonatal conditions, including BPD.
Although the protective effects of MSCs or their exosomes on hyperoxia-induced lung injury have been explored by many researchers, the underlying mechanism has not been addressed in detail, and few studies have focused on their therapeutic benefits on systemic multiple organ injury.
This study aimed to investigate whether intratracheal (iT) administration of human umbilical cord-derived MSCs (hUC-MSCs) could simultaneously attenuate hyperoxia-induced lung, heart, and kidney injuries in an experimental neonatal rat model, and elucidate the underlying regulatory mechanism.
We established an experimental newborn rat model via prolonged exposure to hyperoxia to induce lung, heart, and kidney injury. Briefly, neonatal rats were exposed to hyperoxia (80% O2), treated with hUC-MSCs iT or intraperitoneal (iP) on postnatal day 7 (P7), and harvested on postnatal day 21. The tissue sections of the lung, heart, and kidney were analyzed morphometrically. Protein contents of bronchoalveolar lavage fluid (BALF), pulmonary inflammatory cytokines, myeloperoxidase (MPO) expression, and malondialdehyde (MDA) levels were examined. Furthermore, RNA-sequencing, reverse transcription-quantitative polymerase chain reaction and western blot analysis were performed to explore underlying mechanisms.
The present study showed that the administration of hUC-MSCs on P7 played an essential role in improving pulmonary alveolarization and modulating pulmonary angiogenesis, as well as relieving right ventricular hypertrophy and nephrogenesis impairment in hyperoxia-exposed rats. Rats reared in hyperoxia exhibited a significant increase in BALF protein content, tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6, and macrophage inflammatory protein (MIP)-1α, MIP-1β, MPO and MDA levels, which decreased with hUC-MSC treatment. Additionally, we observed an increase in anti-inflammatory cytokine IL-10 expression in rats that received hUC-MSCs. Transcriptomic analysis showed that hUC-MSCs administration blunted the hyperoxia-induced dysregulated genes, which were enriched in pathways related to inflammatory responses, epithelial cell proliferation, and vasculature development. Moreover, hUC-MSCs increased heme oxygenase (HO-1), JAK2, and STAT3 expression, and their phosphorylation in the lung, heart, and kidney. Remarkably, no significant difference was observed between iT and iP administration.
Our results suggest additional therapeutic effects of hUC-MSCs administration on histological alterations, along with the modulation of inflammatory cell infiltration and oxidative stress in extrapulmonary organs. The therapeutic benefits of local iT instillation are equivalent to those of iP administration in systemic multi-organ damage. These therapeutic effects presumably result from an increase in HO-1 expression and the JAK2/STAT3 signaling pathway.
In future studies, gene expression changes of sorted cell subtypes from multiple organs injured upon hyperoxia exposure will be studied. Further in-depth mechanistic studies are warranted to validate and understand the molecular mechanisms modulated by hUC-MSCs. Moreover, given the significance of changing the MSCs culture mode, the application of genetically modified and three-dimensionally cultured MSCs will be explored to improve therapeutic outcomes in future studies. These studies will lay the foundation for a more extensive and effective clinical application of MSCs in the treatment of BPD.