Unraveling the Appropriate Dose for Infusion of Human Umbilical Cord Blood Derived Mononuclear Cells in Alleviating Hyperoxia Induced Lung Injury in Neonatal Mice

Abstract

\n Background: Intravenous infusion of human umbilical cord blood derived mononuclear cells (hUCB-MNCs) alleviates the hyperoxia-induced neonatal lung injury. The aim of this preclinical study was to determine the optimal dose of hUCB-MNCs in alleviating hyperoxia-induced lung injury in neonatal mice.Method: Newborn C57BL6/J mice were randomly exposed to hyperoxia (85% O2) or normoxia (21% O2) after birth for 14 days. Three different doses of hUCB-MNCs, 3×106 cells/kg (D1), 3×106 cells/kg (D2), and 3×106 (D3), were administered intravenously at postnatal day 7(P7). At P28, lungs were harvested for analyses including morphology for alveolarization, pulmonary function assessment for lung motion and lung blood flow, expression of inflammatory factors and growth factors including TNF-α, IL-1β, IL-6, IL-2, IL-10, MMP9, TGF-β and VEGF. Result: We discovered that hyperoxia-induced lung injuries, such as reduced alveolarization, as evidenced by increased mean chord length (MCL) and radical alveolar area (RAA) and decreased radical alveolar counts (RAC) were significantly restored in D1, D2 and D3, with the best in D3. Enhanced expression of TNF-α, IL-1β, IL-6 concomitant with attenuated expression of IL-10 and IL-2 were shown in all groups with the most significance in D3. Down-regulated expression of TGF-β, MMP9 and up-regulated expression of VEGF in lung tissue were observed in all groups, with the largest extent in D3.Conclusion: Collectively, our study revealed the appropriate dose of intravenous infusion of hUCB-MNCs in alleviating hyperoxia-induced lung injury through modulating inflammatory responses and oxidative stress in neonatal mice.