Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease that is characterized by replacement of the normal lung anatomy with active remodeling and deposition of extracellular matrix (ECM) accompanied by a shift in lung cellular communities. The most common outcome of this debilitating disease is respiratory failure and subsequent death. The disease predominately afflicts the middle aged and elderly and has a median life expectancy after diagnosis of 3.8 yr. Although two FDA-approved drugs consistently slow down disease progression, lung transplantation is still the only curative treatment. Historically, much of our understanding of pulmonary fibrosis has been derived from detailed pathological analysis of human lungs that elucidated the unique morphological characteristics of IPF and observations derived from animal models of disease. In the last decade insights derived from genetic studies and from transcriptomic studies of the human lung have given investigators a better appreciation of the complexity and extent of the molecular and cellular changes that determine the lung phenotype in IPF (11). However, a detailed description of all the cell-specific molecular changes in the human fibrotic lung was until recently still lacking.

The advent of single-cell RNA sequencing (scRNAseq) has afforded researchers the opportunity to comprehensively interrogate tissues at cell-level resolution (8). In contrast to the bulk RNA sequencing protocols that analyzed gene expression in a whole piece of tissue, which averaged the signal of multiple cells without distinction of the cellular source of the signal, scRNAseq profiles expression of each individual cell within a sample. This technology allows researchers to closely examine every single individual cell within a sequenced sample to identify their cell types, functions, and ultimately the molecular signatures and cellular interactions guiding their function within the context of that tissue and human disease. With such breadth and depth, scRNAseq is a powerful tool that is in particular appealing to better untangle the intricate multicellular complexity of the human IPF lung.