Am J Physiol Lung Cell Mol Physiol

. 2021 Aug 25. doi: 10.1152/ajplung.00484.2020. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/34431413/

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

Tram Mai Nguyen ^1 2, Johannes van der Merwe ¹, Linda Elowsson Rendin ³, Anna-Karin Larsson-Callerfelt ³, Jan Deprest ^1 4 5, Gunilla Westergren-Thorsson ³, Jaan Toelen ^1 6Affiliations expand

• PMID: 34431413
• 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 towards AT1. By manipulating ROCK pathway, we demonstrate that stretch-induced Yap/Taz activation promotes alveolar differentiation towards 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.

Keywords: alveolar cell type 1; alveolar development; congenital diaphragmatic hernia; fetal lung stretch; tracheal occlusion.