Intratracheal administration of umbilical cord-derived mesenchymal stem cells attenuates hyperoxia-induced multi-organ injuryviaheme oxygenase-1 and JAK/STAT pathways.

Bronchopulmonary dysplasia (bpd) is not merely a chronic lung disease, but a systemic condition with multiple organs implications predominantly associated with hyperoxia exposure.Despite advances in current management strategies, limited progress has been made in reducing the bpd-related systemic damage.Meanwhile, although the protective effects of human umbilical cord-derived mesenchymal stem cells (h uc-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 the therapeutic effect on systemic multiple organ injury.Aim to investigate whether h uc-msc intratracheal administration could attenuate hyperoxia-induced lung, heart, and kidney injuries and the underlying regulatory mechanisms.Methods neonatal rats were exposed to hyperoxia (80% o2), treated with h uc-mscs intratracheal (i t) or intraperitoneal (i p) on postnatal day 7, and harvested on postnatal day 21.The tissue sections of the lung, heart, and kidney were analyzed morphometrically.Protein contents of the bronchoalveolar lavage fluid (balf), myeloperoxidase (mpo) expression, and malondialdehyde (mda) levels were examined.Pulmonary inflammatory cytokines were measuredviaenzyme-linked immunosorbent assay.A comparative transcriptomic analysis of differentially expressed genes (degs) in lung tissue was conductedvia rna-sequencing.Subsequently, we performed reverse transcription-quantitative polymerase chain reaction and western blot analysis to explore the expression of target m rna and proteins related to inflammatory and oxidative responses.Results i t h uc-mscs administration improved pulmonary alveolarization and angiogenesis (p< 0.01,p< 0.01,p< 0.001, and p< 0.05 for mean linear intercept, septal counts, vascular medial thickness index, and microvessel density respectively).Meanwhile, treatment with h uc-mscs i t ame liorated right ventricular hypertrophy (for fulton's index,p< 0.01), and relieved reduced nephrogenic zone width (p< 0.01) and glomerular diameter (p< 0.001) in kidneys.Among the beneficial effects, a reduction of balf protein, mpo, and mda was observed in h uc-mscs groups (p< 0.01,p< 0.001, and p< 0.05 respectively).Increased pro-inflammatory cytokines tumor necrosis factor-alpha, interleukin (il)-1β, and il-6 expression observed in the hyperoxia group were significantly attenuated by h uc-mscs administration (p< 0.01,p< 0.001, and p< 0.05 respectively).In addition, we observed an increase in anti-inflammatory cytokine il-10 expression in rats that received h uc-mscs i t compared with rats reared in hyperoxia (p< 0.05).Tran scriptomic analysis showed that the degs in lung tissues induced by hyperoxia were enriched in pathways related to inflammatory responses, epithelial cell proliferation, and vasculature development.H uc-mscs administration blunted these hyperoxia-induced dysregulated genes and resulted in a shift in the gene expression pattern toward the normoxia group.H uc-mscs increased heme oxygenase-1 (ho-1), jak2, and stat3 expression, and their phosphorylation in the lung, heart, and kidney (p< 0.05).Remarkably, no significant difference was observed between the i t and i p administration.Conclusion i t h uc-mscs administration ameliorates hyperoxia-induced lung, heart, and kidney injuries by activating ho-1 expression and jak/stat signaling.The therapeutic benefits of local i t and i p administration are equivalent.

Journal: World journal of stem cells (2022)
Publication types: Journal Article