623 - Impact of Prenatal Marijuana Exposure Route on Human Preterm Mesenchymal Stem Cell Therapy in Experimental Bronchopulmonary Dysplasia

Publication Number: 4609.623

Adnan Ismail, CHOC Children's Hospital of Orange County, Irvine, CA, United States; Fayez Bany-Mohammed, University of California, Irvine, Irvine, CA, United States; Cherry Uy, University of California, Irvine, School of Medicine, Orange, CA, United States; Muhammad Aslam, UC Irvine, Orange, CA, United States

Background: Human umbilical cord-derived mesenchymal stem cells (MSCs) show therapeutic potential in experimental bronchopulmonary dysplasia (BPD). Maternal antenatal exposures can affect MSC efficacy. This study evaluated the therapeutic impact of human preterm MSCs harvested from mothers with differing routes of marijuana use.

Objective: We hypothesized that the route of maternal marijuana use at preterm delivery alters the efficacy of MSC-derived exosomes (MSC-exo). We assessed lung function and pulmonary hypertension in hyperoxia-exposed murine models treated with MSC-exo from marijuana-exposed and non-exposed preterm MSCs.

Design/Methods: Maternal marijuana use was determined by positive urine THC screen at delivery. Preterm (24-28 weeks' gestation) umbilical cord MSCs and MSC-exo were generated from 12 marijuana-exposed mothers (4 smoked, 4 topical, 4 oral) and 6 non-exposed controls. MSC-exo content was analyzed for functional differences. FVB mice were exposed to hyperoxia (90% O₂) from birth to day 14, then returned to normoxia. At day 14, animals received 0.1 µg/g MSC-exo via jugular vein. Pulmonary function testing and echocardiography were performed on day 28 to assess BPD.

Results: Marijuana-exposed MSC-exo displayed reduced levels of lung injury- and repair-associated microRNAs. Smoked marijuana exposure led to the greatest reduction, topical exposure the least, and oral exposure intermediate. Correspondingly, MSC-exo from smoked marijuana-exposed MSCs showed loss of therapeutic efficacy, with decreased lung compliance, reduced inspiratory capacity, pulmonary hypertension, and increased right ventricular wall thickness. Topical exposure showed modestly reduced protection, and oral exposure conferred partial benefit (Fig. 1 & 2). All differences were statistically significant.

Conclusion(s): Maternal marijuana use during pregnancy, particularly the route of administration, alters the biological properties and therapeutic efficacy of preterm human umbilical cord-derived MSCs. These findings highlight the importance of maternal exposures in optimizing MSC-based therapies for BPD.

Figure 1
Lung function test via Inspiratory Capacity (IC) and Stat. Compliance (Cst) measurements in Normoxia and Hyperoxia .

Figure 2
Pulmonary hypertension assessment with Echocardiograms in 28-days old mice in Normoxia and Hyperoxia.