Insights gained in the pathology of lung disease through single‐cell transcriptomics

Abstract

The human lung is a relatively quiescent organ in the normal healthy state but contains stem/progenitor cells that contribute to normal tissue maintenance and either repair or remodeling in response to injury and disease. Maintenance or repair lead to proper restoration of functional lung tissue and maintenance of physiological functions, with remodeling resulting in altered structure and function that is typically associated with disease. Knowledge of cell types contributing to lung tissue maintenance and repair/remodeling have largely relied on mouse models of injury‐repair and lineage tracing of local progenitors. Therefore, many of the functional alterations underlying remodeling in human lung disease have remained poorly defined. However, the advent of advanced genomics approaches to define the molecular phenotype of lung cells at single‐cell resolution has paved the way for rapid advances in our understanding of cell types present within the normal human lung and changes that accompany disease. Here we summarize recent advances in our understanding of disease‐related changes in the molecular phenotype of human lung epithelium that have emerged from single‐cell transcriptomic studies. We focus attention on emerging concepts of epithelial transitional states that characterize the pathological remodeling that accompanies chronic lung diseases, including idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, cystic fibrosis, and asthma. Concepts arising from these studies are actively evolving and require corroborative studies to improve our understanding of disease mechanisms. Whenever possible, we highlight opportunities for providing a unified nomenclature in this rapidly advancing field of research. © 2022 The Pathological Society of Great Britain and Ireland.

A human fetal lung cell atlas uncovers proximal-distal gradients of differentiation and key regulators of epithelial fates

“…Single cell mapping of cell states in the adult human lung in health and disease is being performed at increasing resolution (Carraro and Stripp 2022) providing a foundation for understanding lung cellular physiology. The adult lung has low rates of cell turnover (Blenkinsopp 1967; Rawlins and Hogan 2008) making it difficult to capture transition states and progenitor cells.…”

Integrated multiomic analysis identifiesTRIP13as a mediator of alveolar epithelial type II cell dysfunction in idiopathic pulmonary fibrosis

“…AT2 cell marker genes were reduced, while EMT markers were elevated in AT2-IPF cells (37, 38) . Basal- and basaloid-associated cell markers were also elevated in AT2-IPF cells (22) .…”

“…Differentially expressed genes (Table S2) were overrepresented in pathways known to be elevated in IPF (Figure 1C) (33)(34)(35)(36) . Relative gene expression levels for a limited set of genes as markers for AT2-control cells, epithelial to mesenchymal transition (EMT), and basal cells (given the presence of basal-like epithelial cells in IPF (19,21,22) ) are highlighted in Figure 1D. AT2 cell marker genes were reduced, while EMT markers were elevated in AT2-IPF cells (37,38) .…”

“…Single-cell RNA-sequencing (scRNA-seq) analyses of IPF lungs have identified abnormal epithelial cell types co-expressing alveolar and airway (e.g., basal) cell genes, and atypical transitional cells expressing mesenchymal markers (19)(20)(21)(22) . Expression of conducting airway markers in human alveolar epithelial cells (AECs) can be replicated in organoid cultures and is stimulated by TGF-β (21) .…”

Recent Advances in Pathology: the 2022 Annual Review Issue of The Journal of Pathology

“…The use of single cell RNA sequencing is another rapidly expanding field with many applications. Carraro and Stripp at Cedars‐Sinai (Los Angeles, CA, USA) review the use of single cell transcriptomics in lung development and a range of chronic lung pathologies, highlighting the advances in identifying disease‐related changes in epithelial molecular phenotypes, with the emergence of novel epithelial transition states that characterise lung diseases [10]. These exciting advances bring the need for corroborative studies and will require a unified nomenclature in this rapidly maturing research field.…”