Development of a novel humanized mouse model to study bronchopulmonary dysplasia

RationaleThe role of circulating fetal monocytes in bronchopulmonary dysplasia is not known. We utilized a humanized mouse model that supports human progenitor cell engraftment (MISTRG) to test the hypothesis that prenatal monocyte programming alters early lung development and response to hyperoxia.MethodsCord blood-derived monocytes from 10 human infants were adoptively transferred into newborn MISTRG mice at p0 (1 × 106 cells/mouse, intrahepatic injection) followed by normoxia versus hyperoxia (85% oxygen × 14 days). Lungs were harvested at p14 for alveolar histology (alveolar count, perimeter and area) and vascular parameters (vWF staining for microvessel density, Fulton's index). Human CD45 staining was conducted to compare presence of hematopoietic cells. Murine lung parameters were compared among placebo and monocyte-injected groups. The individual profiles of the 10 patients were further considered, including gestational age (GA; n = 2 term, n = 3 moderate/late preterm, and n = 5 very preterm infants) and preeclampsia (n = 4 patients). To explore the monocyte microenvironment of these patients, 30 cytokines/chemokines were measured in corresponding human plasma by multiplex immunoassay.ResultsAcross the majority of patients and corresponding mice, MISTRG alveolarization was simplified and microvessel density was decreased following hyperoxia. Hyperoxia-induced changes were seen in both placebo (PBS) and monocyte-injected mice. Under normoxic conditions, alveolar development was altered modestly by monocytes as compared with placebo (P