Intranasal delivery of human umbilical cord Wharton's jelly mesenchymal stromal cells restores lung alveolarization and vascularization in experimental bronchopulmonary dysplasia

Author:

Moreira Alvaro1,Winter Caitlyn1,Joy Jooby1,Winter Lauryn1,Jones Maxwell1,Noronha Michelle1,Porter Melissa1,Quim Kayla1,Corral Alexis1,Alayli Yasmeen1,Seno Tyrelle1,Mustafa Shamimunisa1,Hornsby Peter1,Ahuja Sunil2

Affiliation:

1. Department of Pediatrics, Cellular and Integrative Physiology University of Texas Health Science Center San Antonio (UTHSCSA), San Antonio, Texas

2. Microbiology and Immunology University of Texas Health Science Center San Antonio (UTHSCSA), San Antonio, Texas

Abstract

Abstract Bronchopulmonary dysplasia (BPD) is a devastating lung condition that develops in premature newborns exposed to prolonged mechanical ventilation and supplemental oxygen. Significant morbidity and mortality are associated with this costly disease and effective therapies are limited. Mesenchymal stem/stromal cells (MSCs) are multipotent cells that can repair injured tissue by secreting paracrine factors known to restore the function and integrity of injured lung epithelium and endothelium. Most preclinical studies showing therapeutic efficacy of MSCs for BPD are administered either intratracheally or intravenously. The purpose of this study was to examine the feasibility and effectiveness of human cord tissue-derived MSC administration given via the intranasal route. Human umbilical cord tissue MSCs were isolated, characterized, and given intranasally (500 000 cells per 20 μL) to a hyperoxia-induced rat model of BPD. Lung alveolarization, vascularization, and pulmonary vascular remodeling were restored in animals receiving MSC treatment. Gene and protein analysis suggest the beneficial effects of MSCs were attributed, in part, to a concerted effort targeting angiogenesis, immunomodulation, wound healing, and cell survival. These findings are clinically significant, as neonates who develop BPD have altered alveolar development, decreased pulmonary vascularization and chronic inflammation, all resulting in impaired tissue healing. Our study is the first to report the intranasal delivery of umbilical cord Wharton's jelly MSCs in experimental BPD is feasible, noninvasive, and an effective route that may bear clinical applicability. Significance statement Bronchopulmonary dysplasia (BPD) is the most common cause of morbidity and mortality in extremely premature neonates. Unfortunately, current therapies for BPD are limited. Preclinical studies have shown that mesenchymal stem cell (MSC) treatment can restore alveolar growth, enhance vascular development, and stimulate tissue repair. Most of these studies have administered the cells via the intravenous/tracheal route. Results of this study show, for the first time to the authors' knowledge, that the intranasal delivery of MSCs for BPD is effective in restoring lung alveolar growth and vascular development. Importantly, this study provides evidence that this noninvasive approach may be given separately or as an adjunct/alternate to other routes.

Funder

Francis Family Foundation

UTHSCSA School of Medicine Clinical Investigator Kickstart Pilot Grant

National Institutes of Health

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,Developmental Biology,General Medicine

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