Uncovering an antifibrotic Prrx1-lineage mesenchymal cell subpopulation in fibrotic lungs.

Idiopathic pulmonary fibrosis (IPF) is a rare and fatal lung disease caused by progressive damage to alveolar epithelial cells, leading to abnormal activation of mesenchymal cells. The PRRX1 transcription factor (TF) has been found to be reactivated in IPF and was previously identified as a key mesenchymal TF in pulmonary fibrosis. In this study, we utilized the Prrx1:CreERT2; Rosa26iTomato murine transgenic line to further characterize the Prrx1-positive cell lineage in healthy and fibrotic lungs. The Prrx1 limb enhancer (Prrx1enh) was undetectable by immunohistochemistry in uninjured lung tissue. However, during the fibrotic phase in the bleomycin model of pulmonary fibrosis, Prrx1enh became activated, marking a population of cells that differentiated into mesenchymal progeny. To investigate further, we conducted reprogramming of these subpopulations after conditional and inducible Prrx1 loss of function. Prrx1 loss in these cells led to worsened fibrosis, indicating that this specific cell population has antifibrotic properties. Our findings reveal a previously unrecognized subpopulation of Prrx1-positive mesenchymal cells that are activated during fibrogenesis. These cells could serve as targets for future therapies aimed at mitigating fibrotic progression in IPF.