Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Attenuate Hyperoxia-Induced Lung Injury in Neonatal Rats

Abstract

Recent evidence suggests mesenchymal stem cells (MSCs) can downmodulate bleomycin-induced lung injury, and umbilical cord blood (UCB) is a promising source for human MSCs. This study examined whether intratracheal or intraperitoneal transplantation of human UCB-derived MSCs can attenuate hyperoxia-induced lung injury in immunocompetent newborn rats. Wild-type Sprague-Dawley rats were randomly exposed to 95% oxygen or air from birth. In the transplantation groups, a single dose of PKH26-labeled human UCBderived MSCs was administered either intratracheally (2 × 10 6 cells) or intraperitoneally (5 × 10 5 cells) at postnatal day (P) 5. At P14, the harvested lungs were examined for morphometric analyses of alveolarization and TUNEL staining, as well as the myeoloperoxidase activity, the level of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and transforming growth factor (TGF)-β mRNA, α-smooth muscle actin (SMA) protein, and collagen levels. Differentiation of MSCs to the respiratory epithelium was also evaluated both in vitro before transplantation and in vivo after transplantation. Despite one fourth dosage of MSCs, significantly more PKH26-labeled donor cells were recovered with intratracheal administration than with intraperitoneal administration both during normoxia and hyperoxia. The hyperoxia-induced increase in the number of TUNELpositive cells, myeloperoixdase activity, and the level of IL-6 mRNA were significantly attenuated with both intratracheal and intraperitoneal MSCs transplantation. However, the hyperoxia-induced impaired alveolarization and increased the level of TNF-α and TGF-β mRNA, α-SMA protein, and collagen were significantly attenuated only with intratracheal MSCs transplantation. MSCs differentiated into respiratory epithelium in vitro and a few PKH26-positive donor cells were colocalized with pro surfactant protein C in the damaged lungs. In conclusion, intratracheal transplantation of human UCB-derived MSCs is more effective than intraperitoneal transplantation in attenuating the hyperoxia-induced lung injury in neonatal rats.Key words: Hyperoxic lung injury; Transplantation; Animal; Newborn; Inflammation; Cell differentiation INTRODUCTION development of hyperoxic neonatal lung injury and BPD (42).Recently, the exogenous administration of bone marBronchopulmonary dysplasia (BPD) is a chronic pulmonary disease that usually occurs in premature infants row (BM)-derived mesenchymal stem cells (MSCs) significantly attenuated the bleomycin-induced lung injury receiving prolonged ventilatory support and oxygen supplementation. It is also an important cause of mortality by downmodulating the inflammatory responses and ameliorating their fibrotic effects (33). In addition, the transand long-term respiratory morbidity with few effective treatments (3,6). The histopathological characteristics of planted cells assumed the lung parenchymal cell phenotypes (34). The anti-inflammatory effect of MSCs has BPD include impaired alveolarization and interstitial fibrosis (30). Prolonged exposure of neonata...

Antenatal betamethasone attenuates intrauterine infection-aggravated hyperoxia-induced lung injury in neonatal rats

“…Hyperoxia-induced lung injury, as demonstrated by decreased alveolarization, a significant increase in the number of TUNEL-positive cells, and increased lung inflammation and resultant collagen deposits, was consistent with the findings in premature human infants with BPD (9), as shown in our previous studies (10,11). Antenatal betamethasone administration significantly reduced lung inflammation at birth as shown by attenuated proinflammatory cytokine levels in P1 rat lungs and subsequently attenuated intrauterine infection-induced aggravation of hyperoxic neonatal lung injuries.…”

“…The lung collagen levels were determined from the total soluble collagen using a Sircol Collagen Assay Kit (Biocolor, Newton Abbey, UK), according to the manufacturer's instructions as previously described (11). The values in the test samples were compared with those obtained with the standard collagen solutions provided by the manufacturer, which were used to construct a standard curve.…”

Mesenchymal Stem Cells for Severe Intraventricular Hemorrhage in Preterm Infants: Phase I Dose-Escalation Clinical Trial

“…Various preclinical data support the therapeutic potential of transplantation with mesenchymal stem cells (MSCs) for treating various intractable neonatal disorders including bronchopulmonary dysplasia (BPD) 11, 12, 13, 14 and hypoxic ischemic encephalopathy (HIE) 15. Human umbilical cord blood (UCB) is a promising source of MSCs.…”

Comparison of Characteristics of Mesenchymal Stem Cells Obtained Mechanically and Enzymatically from Placenta and Umbilical Cord

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