Paracrine stimulation of perinatal lung functional and structural maturation by mesenchymal stem cells

Abstract

Background Mesenchymal stem cells (MSCs) were shown to harbor therapeutic potential in models of respiratory diseases, such as bronchopulmonary dysplasia (BPD), the most common sequel of preterm birth. In these studies, cells or animals were challenged with hyperoxia or other injury-inducing agents. However, little is known about the effect of MSCs on immature fetal lungs and whether MSCs are able to improve lung maturity, which may alleviate lung developmental arrest in BPD. Methods We aimed to determine if the conditioned medium (CM) of MSCs stimulates functional and structural lung maturation. As a measure of functional maturation, Na+ transport in primary fetal distal lung epithelial cells (FDLE) was studied in Ussing chambers. Na+ transporter and surfactant protein mRNA expression was determined by qRT-PCR. Structural maturation was assessed by microscopy in fetal rat lung explants. Results MSC-CM strongly increased the activity of the epithelial Na+ channel (ENaC) and the Na,K-ATPase as well as their mRNA expression. Branching and growth of fetal lung explants and surfactant protein mRNA expression were enhanced by MSC-CM. Epithelial integrity and metabolic activity of FDLE cells were not influenced by MSC-CM. Since MSC’s actions are mainly attributed to paracrine signaling, prominent lung growth factors were blocked. None of the tested growth factors (VEGF, BMP, PDGF, EGF, TGF-β, FGF, HGF) contributed to the MSC-induced increase of Na+ transport. In contrast, inhibition of PI3-K/AKT and Rac1 signaling reduced MSC-CM efficacy, suggesting an involvement of these pathways in the MSC-CM-induced Na+ transport. Conclusion The results demonstrate that MSC-CM strongly stimulated functional and structural maturation of the fetal lungs. These effects were at least partially mediated by the PI3-K/AKT and Rac1 signaling pathway. Thus, MSCs not only repair a deleterious tissue environment, but also target lung cellular immaturity itself.

Development and Functional Characterization of Fetal Lung Organoids

“…Mesenchymal stem cells (MSCs) have demonstrated therapeutic potential in animal models of neonatal lung disease ( 21 – 23 ) and thus represent a promising future therapeutic approach to alleviate disease burden in preterm infants. In our previous study we determined the paracrine effect of MSCs on lung functional and structural development in FDLE cells and fetal lung explants ( 19 ). Herein we aimed at reproducing the reactivity of LOs in comparison to the prior study and to extend the knowledge about cellular effects of MSCs.…”

“…The umbilical cord tissue was collected after delivery from human newborns whose mothers granted informed consent. MSC isolation and characterization are described elsewhere ( 19 ). MSC-CM was produced by incubating the culture medium with MSCs for 72 h, followed by sterile filtration.…”

Epidermal growth factor strongly affects epithelial Na+ transport and barrier function in fetal alveolar cells, with minor sex-specific effects

“…Metabolic activity in male and female FDLE cells stimulated with EGF was determined with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays as described before 31 .…”

Evidence for the Management of Bronchopulmonary Dysplasia in Very Preterm Infants

“…This explains the evident improvement of alveolarization, angiogenesis and pulmonary arterial remodeling by cell-free therapy with MSC-conditioned media in another meta-analysis of preclinical studies [ 237 ]. One very recent study reported on the effect of MSC-conditioned media on structural and functional lung maturation, therefore targeting the lung tissue immaturity itself [ 238 ]. The network-meta-analysis still found MSC therapy superior to MSC-conditioned media regarding all four analyzed clinically relevant outcomes (alveolarization, lung angiogenesis, pulmonary hypertension and lung inflammation) [ 235 ].…”