Stretch increases alveolar type 1 cell number in fetal lungs through ROCK-Yap/Taz pathway.

Tram Mai Nguyen,Johannes Van Der Merwe,Linda Elowsson Rendin,Gunilla Westergren-Thorsson,Jaan Toelen,Anna-Karin Larsson-Callerfelt,Jan Deprest

doi:10.1152/ajplung.00484.2020

Abstract

Accurate fluid pressure in the fetal lung is critical for its development, especially at the beginning of the saccular stage when alveolar epithelial type 1 (AT1) and type 2 (AT2) cells differentiate from the epithelial progenitors. Despite our growing understanding of the role of physical forces in lung development, the molecular mechanisms that regulate the transduction of mechanical stretch to alveolar differentiation remain elusive. To simulate lung distension, we optimized both an ex vivo model with precision cut lung slices and an in vivo model of fetal tracheal occlusion. Increased mechanical tension showed to improve alveolar maturation and differentiation toward AT1. By manipulating ROCK pathway, we demonstrate that stretch-induced Yap/Taz activation promotes alveolar differentiation toward AT1 phenotype via ROCK activity. Our findings show that balanced ROCK-Yap/Taz signaling is essential to regulate AT1 differentiation in response to mechanical stretching of the fetal lung, which might be helpful in improving lung development and regeneration.

Highlights

Lung morphogenesis is a highly harmonized process characterized by sequential developmental stages
We found that mechanical distension during the canalicular/saccular stage of lung development promotes alveolar type 1 (AT1) cell differentiation where Rho-associated protein kinase (ROCK)-induced Yap/Taz activation was shown to play an important role
precision-cut lung slices (PCLS) were cultured for 24 h to enable the analyses of morphometry, immunohistochemistry, and real-time quantitative PCR (RT-qPCR) (Fig. 1)

Summary

Introduction

Lung morphogenesis is a highly harmonized process characterized by sequential developmental stages. Around gestation day 16.5 or E16.5, the murine lung converts from a branching process toward an alveolar epithelial differentiation stage. Distal epithelial progenitors start to differentiate into bipotent alveolar epithelial progenitors that can give rise to alveolar type 1 (AT1) and 2 (AT2) epithelial cells [1, 2]. In preparation for the lungs to transform from a liquid-filled to an air-exposed organ, this process is critical as it marks the start of respiratory epithelium formation where gas exchange takes place after birth. One of the mechanisms that has shown to influence the differentiation from bipotent progenitor cells into either AT1 or AT2 is mechanical stretch [5,6,7]. The exact physiological process by which stretch is converted into differential cell division is still not fully understood

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Discussion

Conclusion