Allogeneic administration of human umbilical cord-derived mesenchymal stem/stromal cells for bronchopulmonary dysplasia: preliminary outcomes in four Vietnamese infants

(2020) 18:398 Nguyen et al. J Transl Med https://doi.org/10.1186/s12967-020-02568-6 Journal of Translational Medicine Open Access RESEARCH Allogeneic administration of human umbilical cord‑derived mesenchymal stem/ stromal cells for bronchopulmonary dysplasia: preliminary outcomes in four Vietnamese infants Liem Thanh Nguyen1†, Thai T. H. Trieu2†, Hue T. H. Bui3†, Van T. Hoang4, Anh T. T. Nguyen3, Nhung T. H. Trinh3, Kien T. Nguyen1 and Duc M. Hoang1,4*† Abstract Background: Bronchopulmonary dysplasia (BPD) is a severe condition in premature infants that compromises lung function and necessitates oxygen support. Despite major improvements in perinatal care minimizing the devastating effects, BPD remains the most frequent complication of extreme preterm birth. Our study reports the safety of the allogeneic administration of umbilical cord-derived mesenchymal stem/stromal cells (allo-UC-MSCs) and the progression of lung development in four infants with established BPD. Methods: UC tissue was collected from a healthy donor, followed by propagation at the Stem Cell Core Facility at Vinmec Research Institute of Stem Cell and Gene Technology. UC-MSC culture was conducted under xeno- and serum-free conditions. Four patients with established BPD were enrolled in this study between May 25, 2018, and December 31, 2018. All four patients received two intravenous doses of allo-UC-MSCs (1 million cells/kg patient body weight (PBW) per dose) with an intervening interval of 7 days. Safety and patient conditions were evaluated during hospitalization and at 7 days and 1, 6 and 12 months postdischarge. Results: No intervention-associated severe adverse events or prespecified adverse events were observed in the four patients throughout the study period. At the time of this report, all patients had recovered from BPD and were weaned off of oxygen support. Chest X-rays and CT scans confirmed the progressive reductions in fibrosis. Conclusions: Allo-UC-MSC administration is safe in preterm infants with established BPD. Trial registration This preliminary study was approved by the Vinmec International Hospital Ethics Board (approval number: 88/2019/QĐ-VMEC; retrospectively registered March 12, 2019). Keywords: Bronchopulmonary dysplasia, Umbilical cord tissue, Allogeneic mesenchymal stem cell administration *Correspondence: † Nguyen L.T, Thai T.H. Trieu, Hue T.H. Bui and Duc M. Hoang contributed equally to the work. 1 Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam Full list of author information is available at the end of the article Background First discovered in 1967, bronchopulmonary dysplasia (BPD) has since emerged as the most prevalent chronic lung disorder in premature infants, resulting in reductions in alveolarization, vascular growth and overall lung function [1]. According to the National Institute of © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativeco mmons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Nguyen et al. J Transl Med (2020) 18:398 Child Health and Human Development (NICHD), BPD is defined as a persistent parenchymal lung disease in preterm infants (< 32 weeks gestational age) with radiographic confirmation, and at 36 weeks postmenstrual age, BPD requires oxygen support for more than 3 consecutive days to maintain arterial oxygen saturation in the 90–95% range [2]. The pathological hallmarks of BPD involve disruption of lung development, impaired alveolarization and interstitial fibrosis due to antenatal (intrauterine growth restriction, maternal smoking) and/ or postnatal risk factors (mechanical ventilation, oxygen toxicity, and infection) [3, 4]. BPD commonly occurs in preterm infants who weigh less than 1000 g, are born at 24–26 weeks of gestation and require prolonged mechanical ventilation and oxygen support [5]. Infants at less than 30 weeks gestational age are at a particularly high risk for immature respiratory system development and suffer from detrimental long-term outcomes, including high morbidity and mortality rates. In the last 50 years, advances in neonatal medicine, including the discovery of neonatal steroid treatments, which were proven to be associated with glucocorticoid-related brain injury as major side effect [6–8], surfactants [9–11], gentle ventilation treatments [12, 13], and effective noninvasive ventilation devices, have significantly improved the clinical outcomes in premature newborns with BPD. However, the rates of complications and mortality are still high among infants with BPD [14]. Recently, MSC therapy was used to treat BPD in an animal model. Proof-of-concept experiments in neonatal BPD rodent models demonstrated that the injection of bone marrow mesenchymal stem cells (BM-MSCs) via either the intravenous (IV) or intratracheal route had lung-protective functions, including reducing lung inflammation and pulmonary hypertension and reforming the alveolar structure, subsequently improving the survival rate [15–18]. Furthermore, a single dose of human UC-MSCs administered intratracheally prevented and rescued neonatal rats from hyperoxia-induced lung damage [19]. In humans, Ahn and colleagues conducted the first phase I clinical trial using umbilical cord bloodderived MSC (UCB-MSC) administration to prevent the manifestation of BPD in premature infants in 2014. Their results confirmed that UCB-MSC administration was safe in premature infants at risk of BPD development [20]. In 2017, our group reported the first patient with established BPD treated successfully with autologous bone marrow mononuclear cells [21]. However, obtaining bone marrow from established BPD newborns in critical condition is challenging and carries a major risk of pulmonary complications. Therefore, this study was performed to evaluate the safety of allogeneic administration of UC-MSCs based on their immunoprivilege Page 2 of 12 features and eliminate the need for bone marrow aspiration in infants with established BPD. We hypothesized that allo-U (...truncated)