Microfluidic chest cavities reveal that transmural pressure controls the rate of lung development

Abstract

Mechanical forces are increasingly recognized to regulate morphogenesis, but how this is accomplished in the context of the multiple tissue types present within a developing organ remains unclear. Here, we use bioengineered 'microfluidic chest cavities' to precisely control the mechanical environment of the fetal lung. We show that transmural pressure controls airway branching morphogenesis, the frequency of airway smooth muscle contraction, and the rate of developmental maturation of the lungs, as assessed by transcriptional analyses. Time-lapse imaging reveals that branching events are synchronized across distant locations within the lung, and are preceded by long-duration waves of airway smooth muscle contraction. Higher transmural pressure decreases the interval between systemic smooth muscle contractions and increases the rate of morphogenesis of the airway epithelium. These data reveal that the mechanical properties of the microenvironment instruct crosstalk between different tissues to control the development of the embryonic lung.

The Mechanosensitive Ion Channel TRPV4 is a Regulator of Lung Development and Pulmonary Vasculature Stabilization

“…The presence of TRPV4 at the apical surface may serve to sense these deformations and regulate cellular behaviors necessary for the formation of new airways. This would be consistent with numerous studies that demonstrate increased airway branching with ASM contraction frequency and an arrest in airway branching with the absence of ASM contractions 16,31,50 . Further, localization to the subepithelial mesenchyme and to the pulmonary vasculature, at an embryonic stage where the ASM and vasculature are rapidly assembling, suggests TRPV4 may regulate the differentiation, assembly, or function of these critical tissues.…”

“…Building on the findings supporting the role of TRPV4 as a pressure sensitive Ca 2+ channel, and our recent study demonstrating pressure-based regulation of airway contractility 50 , we hypothesized that TRPV4 mediates the peristaltic ASM contractility of the lung. High-frequency timelapse imaging (1 Hz) was used to observe lung explants following 48 hours of culture ( Supplementary Movie 1 ).…”

“…This differential pressure acting on the developing airways, termed transmural pressure, has been long suspected to be essential for lung growth. Increasing fluid retention or transmural pressure results in airway elaboration 3,50,63 , and relieving fluid pressure results in reduced airway growth 3,18 . This quasistatic pressure is coupled to active contractility at the cellular level 37,43,44 .…”

3D organ models—Revolution in pharmacological research?

“…The physical properties of the tissue microenvironment, as well as the external forces that act upon them, alter cell behaviors, tissue organization and cell-generated forces. Hence, mechanical forces are important for tissue development as demonstrated for several organs including the lung [74] and skin [75]. In addition, the development of human disease models per se are still in their infancy.…”

Morphogenesis one century afterOn Growth and Form

“…The mechanics of developmental processes involves multiple scales, and a number of papers discuss examples of this: Boselli and colleagues consider the role of fluid flows and shear stress in orienting tissue movements (Boselli et al, 2017), Nelson and colleagues look at the effects of pressure on early branching processes (Nelson et al, 2017), Ruiz-Herrero and colleagues provide a general framework for size control of growing tissue cysts (Ruiz-Herrero et al, 2017), Lefevre and colleagues analyse multiscale branching in the mammalian kidney (Lefevre et al, 2017), and axis elongation in the avian embryo is the focus of the work of Bénazéraf and colleagues (Bénazéraf et al, 2017).…”