STAT3 Promotes Alveolar Epithelial Regeneration After Acute Lung Injury

Abstract

Regenerating new alveolar epithelium is essential for recovery from many common and devastating lung diseases including pneumonia, influenza, and the acute respiratory distress syndrome. The regenerative process occurs when type II alveolar pneumocytes (AT2) transform from quiescent surfactant-producing cells into adult stem cells capable of generating new AT2 cells and type I alveolar pneumocytes. Here we use a genome-wide analysis of chromatin accessibility to elucidate how the AT2 cell restores alveolar homeostasis following acute lung injury. Our data show that the chromatin architecture of AT2 cells is significantly altered following acute lung injury. Newly accessible chromatin binding sites allow phosphorylated signal transducer and activator of transcription 3 (STAT3) to control essential regenerative pathways in AT2 cells. We observed that loss of STAT3 signaling in AT2 cells prevents development of alveolar organoids in vitro and efficient restoration of alveolar structures following both sterile and infectious lung injuries in vivo. Collectively, these data highlight the importance of the STAT3 transcription factor in orchestrating alveolar epithelial regeneration.