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

Jia Chen,Zhichun Feng,Xue Wang,Xue Du,Xiao Yang,Yuhan Chen,Guojun Liu,Xiaowei Fei,Fengjun Xiao,Xing Zhang,Jian Ru Peng

doi:10.3389/fcell.2021.679866

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.

Highlights

Bronchopulmonary dysplasia (BPD) is the most common complication associated with extremely preterm infants and is increasing in prevalence, most likely due to the increased survival of extremely low gestational age newborns (Thebaud et al, 2019)
Accumulating evidence has suggested that human mesenchymal stem cells (MSCs) can possess the potential to facilitate tissue repair and stimulate lung maturation (Laube et al, 2016), while limited preclinical experiments have demonstrated that Umbilical Cord-Derived Mesenchymal Stem Cells (UC-MSCs) can improve outcomes under hyperoxia-induced BPD
Considering the side effects of metastatic potential and EMT property raised by human MSC implantation in tumor treatment (Yan et al, 2021), mononuclear cells (MNCs) are optimal alternatives in stem cell-based therapies, especially cord blood-derived mononuclear cells (CB-MNCs), among which we have witnessed an increasing body of data (Yin et al, 2015; Shin et al, 2016)

Summary

Introduction

Bronchopulmonary dysplasia (BPD) is the most common complication associated with extremely preterm infants and is increasing in prevalence, most likely due to the increased survival of extremely low gestational age newborns (Thebaud et al, 2019). Developing novel and efficient therapies to reduce overall morbidity and mortality in preterm infants with BPD is of great significance. Recent data from allogeneic or autologous umbilical cord-derived MSC-based therapies have demonstrated promising results in studies based on animal models and early phase clinical studies of neonatal lung injury (Kang and Thébaud, 2018). It is worthwhile to determine the regulatory functions of human cord blood MNCs in an animal model. It is still hung in the balance whether a specific type of stem cell is the best candidate for a particular application in a certain disease model; comparison of the efficacies of UC-MSCs and CB-MNCs in preventing BPD is of great significance

Methods

Results

Conclusion