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

Janine Obendorf,Claire Fabian,Mandy Laube,Ulrich H Thome

doi:10.1186/s13287-020-02028-4

Janine Obendorf, Claire Fabian + Show 2 more

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https://doi.org/10.1186/s13287-020-02028-4

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Abstract

BackgroundMesenchymal 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.MethodsWe 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.ResultsMSC-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.ConclusionThe 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.

Highlights

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
MSC-conditioned medium (CM) induces functional maturation of fetal distal lung epithelial cells (FDLE) cells Mesenchymal stem cellconditioned medium (MSC-CM) incubation of FDLE cells for 24 h significantly elevated Basal current (Ibase) and Amiloride-sensitive ΔISC (ΔIamil) 1.4-fold compared with control cells (p < 0.001, Fig. 1a)
Restored alveolar fluid clearance (AFC) was shown by MSCs and their microvesicles in the lungs that were rejected for transplantation [68, 69]. These studies are in line with our results; they were conducted in challenged models or diseased transplants, whereas we show a stimulating effect of MSC-CM on Na+ transport in undamaged fetal alveolar cells

Summary

Introduction

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. Growth factor signaling as well as ion channel functions are crucially involved in intrauterine lung proliferation and differentiation. Fluid transport across alveolar epithelial cells is mediated by Na+ influx through epithelial Na+ channels (ENaC) in the apical membrane [2]. Disruption of Na+ transport-driven alveolar fluid clearance (AFC) and insufficient surfactant secretion due to preterm birth can lead to serious pulmonary complications and respiratory distress

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