P0778 - Wharton’s Jelly Mesenchymal Stem Cell-derived (WJ-MSC) exosomes for Severe Bronchopulmonary Dysplasia: A Dose-Finding Study

Background:
Previously, we demonstrated that early administration of Wharton’s Jelly Mesenchymal Stem Cell-derived (WJ-MSC) exosomes attenuates pulmonary hypertension (PH) and improves lung structure in experimental bronchopulmonary dysplasia (BPD). The optimal dose is however not known. The purpose of this study was to determine the optimal WJ-MSC exosome dose for lung regeneration in severe BPD complicated by PH.

Objective: To elucidate the most effective and safe MSC exosome dose to prevent neonatal hyperoxia-induced lung injury and PH.

Design/

Methods: Newborn Sprague-Dawley rats (N=75) exposed to normoxia (RA) or hyperoxia (85% O2; HYP) from postnatal day (P) 1- P14 were randomly assigned to receive varying doses of intra-tracheal (IT) WJ-MSC derived exosomes (low dose: 2 x 108; medium dose: 12 x 108 ; high dose: 60 x 108 particles per gram body weight in 50 ul) or exosome free media (PL) on P3. The degree of pulmonary hypertension (PH), vascular remodeling, alveolarization, as well as lung angiogenesis was assessed at P14. PH was determined by measuring right ventricular systolic pressure (RVSP) and pulmonary vascular remodeling was evaluated by quantifying the percentage of muscularized peripheral pulmonary vessels. Right ventricular hypertrophy (RVH) was determined by right ventricle to left ventricle plus septum weight ratio (RV/LV+S). Alveolarization was evaluated by measuring mean linear intercept (MLI) and radial alveolar count (RAC). Angiogenesis was determined by measuring vascular density. Data are expressed as mean ± SD, and analyzed by ANOVA.

Results: Exposure of neonatal rats to hyperoxia impaired lung alveolarization as evidenced by increased MLI and reduced RAC (Table 1). This was accompanied decreased vascular density and increased percent muscularized vessels (Table 1). In contrast, IT administration of low, medium or high dose WJ-MSC exosomes significantly improved alveolar structure, vascular density and pulmonary vascular remodeling and there was no difference in beneficial effects among the three doses (Table 1). Moreover, whereas hyperoxia-PL exposed animals had increased RVSP and RV/LV+S and decreased survival, IT administration of all three WJ-MSC exosome doses significantly attenuated PH and RVH (Table 1 and Fig 1). However, only high dose WJ-MSC exosome improved survival (Fig 1).

Conclusion:
In an experimental model of severe BPD, IT WJ-MSC exosomes preserves lung structure, attenuates PH and improves survival in a non-dose dependent manner.