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

Background: BPD is a common pulmonary complication seen in preterm infants which has a multifactorial pathogenesis. Current strategies, albeit successful in moderately reducing morbidity and mortality of BPD, failed to draw overall satisfactory conclusion. Meanwhile, a substantial studies have reported the altered expression profile of microRNA and lncRNA in the pathogenesis of BPD, while detailed circRNA profile as well as comprehensive lncRNA-miRNA-mRNA and circRNA-miRNA-mRNA networks are largely unknown. Methods: Male C57BL6/J newborn pups were exposed to 85% O2 to construct the hyperoxia BPD model and CB-MNCs or UC-MSCs Cells were intravenously injected at PN7 thereafter. Growth rate was recorded, lung morphology were determined by HE staining and transmission electron microscopy, pulmonary function alterations were defined by respiratory function test and cardiovascular-pulmonary function assessment, reshaped expression of cytokines were evaluated by qPCR and immunohistochemistry approach. The underlying mechanism based on theory of ceRNA network were elucidated by whole transcriptome sequencing. Findings: Both CB-MNC and UC-MSC are efficient in alleviating BPD, verified by our mice model mimicking moderate and severe BPD. Notably, CB-MNC implantation have more prominent effects preventing alveolar simplification and pulmonary vessel loss, restoring pulmonary respiratory functions and reshaping inflammatory responses. Moreover, we further systematically investigated the expression profiles of mRNA, miRNA, lncRNA and circRNA. Importantly, those unique alterations induced by transplantation of different stem cells were highly enriched in the processes related to regulation of RhoGTPase activity, chromosome regulation and cell cycle control. Finally, we illustrate the comprehensive mRNA-miRNA-lncRNA and mRNA-miRNA-circRNA networks. Funding: This research was jointly granted by National Key R&D Program of China (2017YFC1001701, 2018YFC1002701) and Chinese National Natural Science Foundation Projects (81901518). Conflict of Interest: All authors declared that they had no competing conflicts of interests to disclose. Ethical Approval: Animal procedures were reviewed and approved by the Animal Care and Ethic Committee of seventh medical center of PLAGeneral Hospital (No. 2020-037). All animals were housed, cared for, and used in compliance with the guidelines regarding the humane use and care of laboratory animals for biomedical research published by the National Institutes of Health (No.85-23, revised 1996).