Intratracheal Transplantation of Amnion-Derived Mesenchymal Stem Cells Ameliorates Hyperoxia-Induced Neonatal Hyperoxic Lung Injury via Aminoacyl-Peptide Hydrolase

Abstract

Background and Objectives: Bronchopulmonary dysplasia (BPD) has major effects in premature infants. Although previous literature has indicated that mesenchymal stem cells (MSCs) can alleviate lung pathology in BPD newborns and improve the survival rate, few research have been done investigating significantly differentially expressed genes in the lungs before and after MSCs therapy. The aim of this study is to identify differentially expressed genes in lung tissues before and after hAD-MSC treatment. Methods and Results: Human amnion-derived MSCs (hAD-MSCs) were cultured and met the MSCs criteria for cell phenotype and multidirectional differentiation. Then we confirmed the size of hAD-MSCs-EXOs and their expressed markers. An intratracheal drip of living cells showed the strongest effect on NHLI compared to cellular secretions or exosomes, both in terms of ameliorating pulmonary edema and reducing inflammatory cell infiltration. Through gene chip hybridization, PCR, and western blotting, acylaminoacyl-peptide hydrolase (APEH) expression was found to be significantly decreased under hyperoxia, and significantly increased after hAD-MSC treatment. Conclusions: The intratracheal transplantation of hAD-MSCs ameliorated NHLI in neonatal rats through APEH.

Characteristics and Therapeutic Potential of Human Amnion-Derived Stem Cells

“…Likewise, hAESCs derived from term-pregnancy were able to activate bronchioalveolar stem cells and type 2 alveolar epithelial cells compared to preterm-pregnancy hAESCs following bleomycin challenge [ 130 ]. At the genetic level, Li et al observed that hAMSCs ameliorated hyperoxia-induced neonatal lung injury with a significant increased expression of aminoacyl-peptide hydrolase [ 131 ]. In addition, epithelial disruption by polidocanol provided a new effective way for intratracheal transplantation of human amniotic stem cells [ 132 ].…”

MSC Based Therapies to Prevent or Treat BPD—A Narrative Review on Advances and Ongoing Challenges

“…This allows the conclusion that the intranasal route is principally feasible but effects are more pronounced when direct routes are used. Beneficial effects were obtained mainly for umbilical cord and bone marrow derived MSC but three studies investigated placental tissue derived MSC and two studies amniotic fluid or amniotic membrane derived MSC with improvements in classical hallmarks of MSC action (compiled within Table 2 ) [ 47 , 52 , 64 ]. Only one study investigated MSC from different origin and reported MSC derived from the umbilical cord superior to MSC from adipose tissue ( Table 4 ) [ 33 ].…”

“…Two other settings were unable to display differences in outcome [ 45 , 53 , 61 ]. One study using EV derived from adipose tissue MSC revealed reduced efficacy compared to the direct cell application that argues towards an in-depth comparison of preparations before using them in clinical settings [ 64 ]. These data suggest a thorough evaluation of EV potency needs to be conducted when comparing different treatment approaches.…”

Effects of Mesenchymal Stromal Cell-Derived Extracellular Vesicles in Lung Diseases: Current Status and Future Perspectives

“…In preclinical studies, newborn mice or rats exposed to a hyperoxia (75%) microenvironment are widely used to mimic the pathogensis of human BPD [27]. Over the years, systematic administration, or local injection (intranasal [28] or intratracheal [29]) of MSCs have defined the beneficial impact on attenuating experimental BPD through inhibition of Nmethyl-D-aspartic acid (NMDA) receptors [30], reninangiotensin system (RAS) [31], TLR4 expression [32], decorin [29] and CTGF secretion [33], accompanied by upregulating the production of aminoacyl-peptide hydrolase [34], PTX3 [35], VEGF [33], stromal cell-derived factor 1 [36], macrophage stimulating factor 1 [37], and osteopontin [37], leading to increased survival rate, downregulated inf lammation-and hyperoxia-induced defect ive alveolarization, and reduced lung fibrosis in experimental BPD mice. Moreover, MSC stably transfected with a truncated version of CC chemokine ligand 2 (CCL2) promotes macrophage activation, and is seen to be more effective than MSCs alone [38].…”