According to a recent studies using Single-Cell RNA-Sequencing Technologies, when lung cells are damaged, AT2 cells act as stem cells, proliferate themselves and differentiate into AT1 cells through intermediate stage precursor cells (Krt8+ ADI) in the process of alveolar regeneration.* In Hypoxia the precursor cells do not differentiate into AT1 cells and cause fibrosis by HIF-1α/Notch signaling. While HIF-1α activity is suppressed, it is differentiated into AT1 cells by Wnt signaling.** These studies indicate that HIF-1α is potentially a trigger to induce the precursor cells to fibrosis.
* Strunz et al (2020) Nature commun., Alveolar regeneration through a Krt*+ transitional stem cell state that persists in human lung fibrosis
* Xi et al. (2017) Nature cell biol. Local lung hypoxia determines epithelial fate decisions during alveolar regeneration
single-cell RNA-sequencing (scRNA-seq)