Identifying donor-dependent differences in the ability of umbilical cord msc to attenuate lung injury in a hyperoxic rodent bronchopulmonary dysplasia model

Abstract

Background & Aim The chronic lung disease bronchopulmonary dysplasia (BPD) is the most severe complication of prematurity. BPD occurs following ventilator treatment with supplemental oxygen for acute respiratory failure, and early inflammation. The hallmarks of the lung pathology are arrested lung development including fewer and larger alveoli with less septation, thickening of alveolar septa and impaired development of the capillary network. These changes may lead to life-long respiratory morbidity including asthma, reduced exercise capacity, early onset emphysema and pulmonary hypertension. Currently, there is no treatment for BPD. Mesenchymal stromal cells derived from the umbilical cord (UC-MSCs) improve lung structure and function in experimental BPD, and early phase clinical trials are underway. However, the optimal UC-MSC donor remains to be determined. The aim of this project is to compare healing effects of UC-MSC donors in hyperoxia-induced experimental BPD. Methods, Results & Conclusion UC-MSCs derived from 5 human donors (1st term delivery [TMSC], 2nd term delivery [T2MSC], preterm delivery [PMSC], preterm delivery with preeclampsia [PPMSC], preterm delivery with chorioamnionitis [PCMSC]) were administered intratracheally at postnatal day (P) 4 in rat pups exposed to 85% oxygen from P0 to P14. At P21, survival, lung function (flexivent), lung structure (mean linear intercept), right ventricular hypertrophy (Fulton index), as well as lung vasculature at P35 (microCT) were assessed. Treatment with UC-MSCs increased survival in hyperoxia-exposed developing pups. In addition, TMSC, PMSC, PPMSC and PCMSC, but not T2MSC, improved lung compliance, lung growth and attenuated pulmonary hypertension when compared to control hyperoxic pups. Thus, donor source impacts beneficial effects of UC-MSCs in a rat BPD model. In the future, understanding the differences at the transcriptomic level between UC-MSC donors might improve the identification of the optimal MSC source for treatment of complications of extreme prematurity, the number one killer of infants below the age of 5.