Integrative Studies of Human Cord Blood Derived Mononuclear Cells and Umbilical Cord Derived Mesenchyme Stem Cells in Ameliorating Bronchopulmonary Dysplasia

Abstract

Bronchopulmonary dysplasia (BPD) is a common pulmonary complication observed in preterm infants that is composed of multifactorial pathogenesis. Current strategies, albeit successful in moderately reducing morbidity and mortality of BPD, failed to draw overall satisfactory conclusion. Here, using a typical mouse model mimicking hallmarks of BPD, we revealed that both cord blood-derived mononuclear cells (CB-MNCs) and umbilical cord-derived mesenchymal stem cells (UC-MSCs) are efficient in alleviating BPD. Notably, infusion of CB-MNCs has more prominent effects in preventing alveolar simplification and pulmonary vessel loss, restoring pulmonary respiratory functions and balancing inflammatory responses. To further elucidate the underlying mechanisms within the divergent therapeutic effects of UC-MSC and CB-MNC, we systematically investigated the long noncoding RNA (lncRNA)–microRNA (miRNA)–messenger RNA (mRNA) and circular RNA (circRNA)–miRNA–mRNA networks by whole-transcriptome sequencing. Importantly, pathway analysis integrating Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG)/gene set enrichment analysis (GSEA) method indicates that the competing endogenous RNA (ceRNA) network is mainly related to the regulation of GTPase activity (GO: 0043087), extracellular signal-regulated kinase 1 (ERK1) and ERK2 signal cascade (GO: 0070371), chromosome regulation (GO: 0007059), and cell cycle control (GO: 0044770). Through rigorous selection of the lncRNA/circRNA-based ceRNA network, we demonstrated that the hub genes reside in UC-MSC- and CB-MNC-infused networks directed to the function of cell adhesion, motor transportation (Cdk13, Lrrn2), immune homeostasis balance, and autophagy (Homer3, Prkcd) relatively. Our studies illustrate the first comprehensive mRNA–miRNA–lncRNA and mRNA–miRNA–circRNA networks in stem cell-infused BPD model, which will be valuable in identifying reliable biomarkers or therapeutic targets for BPD pathogenesis and shed new light in the priming and conditioning of UC-MSCs or CB-MNCs in the treatment of neonatal lung injury.

Umbilical cord blood-derived therapy for preterm lung injury: a systematic review and meta-analysis

“… 48 , 51 , 53 , 55 All 8 papers that analyzed for a difference in the survival of animals receiving UCB-derived therapy compared to injury controls reported no significant difference. 39 , 40 , 42 , 46 , 47 , 49 , 52 , 60 Thirteen preclinical studies reported the outcome of weight in UCB-derived therapy group versus injury control group. Six of the 13 studies reported a statistically significant difference in favor of UCB-derived therapy administration being associated with a higher weight when compared to the injury control group.…”

“… 39 , 41 , 42 , 51 , 52 , 55 , 56 Finally, 8 preclinical studies investigated other safety effects associated with the administration of UCB. 39 , 43-45 , 49 , 51 , 55 , 57 Two of the 8 studies reported a difference in safety effects. De Paepe et al observed lung tumors in 1 normal control mouse and 2 preterm lung injury mice which received UCB-derived CD34 + cells.…”

“… 55 The remaining 6 studies which investigated adverse safety effects, observed no abnormal findings. 39 , 43 , 44 , 49 , 57 …”

Early prediction of bronchopulmonary dysplasia: can noninvasive monitoring methods be essential?

“…Mesenchymal stromal cells (MSCs) isolated from TA of newborns express lung-specific genes, differ from lung fibroblasts, and produce proinflammatory cytokines [ 92 ]. In a newborn mouse lung injury model, intravenous or intra-alveolar MSCs transplantation was related to decreased inflammation and fibrosis in the lung [ 93 ]. The colony/cluster ratio of MSCs in the TA was considerably lower in BPD infants, according to a cross-sectional investigation (p=0.002).…”

Effects of human umbilical cord blood mononuclear cells on ovalbumin-induced asthma in mice

“…Compared with MNCs obtained from adult bone marrow MNCs (BMMNCs), umbilical cord blood MNCs (UCMNCs) have higher cell viability and lower reaction to cytotoxic T cells and T-helper (Th)1 cells ( 5 ). The therapeutic potential of UCMNCs has been reported in many animal models involving bronchopulmonary dysplasia ( 6 ), neonatal lung injury ( 7 ), and acute myocardial infarction ( 8 ), and in some clinical studies for diseases such as multiple system atrophy ( 9 ) and spastic cerebral palsy ( 10 ). The non-invasiveness, high accessibility, and few ethical constraints of UCMNCs make them a suitable alternative to BMMNCs.…”