Editors' ChoiceIdiopathic Pulmonary Fibrosis

“Gli”-ful neighbors induce epithelial metaplasia

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Science Translational Medicine  25 Nov 2020:
Vol. 12, Issue 571, eabf7103
DOI: 10.1126/scitranslmed.abf7103

Abstract

Gli1+ mesenchymal stromal cells induce epithelial metaplasia.

Although essential to tissue homeostasis, the repair process after tissue damage also results in scarring or fibrosis and other maladaptive responses. Epithelial metaplasia, the emergence of an ectopic type of epithelial cells in place of another, is one such result. Epithelial metaplasia most characteristically noted in precancerous lesions is also a cardinal feature of idiopathic pulmonary fibrosis (IPF), a complex multifactorial disease with limited therapeutic options. In several instances, IPF lungs demonstrate widespread “bronchiolization” wherein airway cells replace gas-exchanging alveolar areas, which adversely affects lung function.

In this elegant study, Cassandras et al. investigated the microenvironment or niche surrounding epithelial cells that promotes metaplasia. Using a bleomycin-induced model of fibrosis, they discovered that certain mesenchymal stromal cells expressing Gli1 (Gli1+ cells) are pivotal for the pathological epithelial reprogramming. By activating hedgehog signaling, these Gli1+ cells suppressed bone morphogenetic protein (BMP) pathways. This mechanism provided a microenvironment immediately surrounding the Krt5+ basal (epithelial) cells that promoted metaplasia. They were able to rescue this phenotype by exogenously supplied BMP, which not only inhibited the metaplastic conversion but also promoted differentiation into type 2 alveolar cells, which express surfactant protein C (SFTPC+). SFTPC+ cells not only constitute an important part of the gas-exchanging units called “alveoli” but can also self-renew and give rise to type 1 alveolar epithelial cells. Finally, they were able to demonstrate the imbalance in the BMP signaling pathway in single-cell RNA-sequencing from lungs of patients with IPF compared with autopsy-derived control tissue. Because the IPF lungs were from patient undergoing lung transplantation, it raises questions about the timing of the BMP signaling changes—whether it is the cause or a consequence of this complex disease process. However, the mechanistic animal work does provide a sound argument for pursuing therapeutic avenues targeting these pathways.

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