Lung Pericytes and Resident Fibroblasts: Busy Multitaskers

Abstract

Pericytes, resident fibroblasts, and mesenchymal stem cells are poorly described cell populations. They have recently been characterized in much greater detail in rodent lungs and have been shown to play important roles in development, homeostasis, response to injury and pathogens, as well as recovery from damage. These closely related mesenchymal cell populations form extensive connections to the lung's internal structure, as well as its internal and external surfaces. They generate and remodel extracellular matrix, coregulate the vasculature, help maintain and restore the epithelium, and act as sentries for the immune system. In this review, we revisit these functions in light of significant advances in characterizing and tracking lung fibroblast populations in rodents. Lineage tracing experiments have mapped the heritage, identified functions that discriminate lung pericytes from resident fibroblasts, identified a subset of mesenchymal stem cells, and shown these populations to be the predominant progenitors of pathological fibroblasts and myofibroblasts in lung diseases. These findings point to the importance of resident lung mesenchymal populations as therapeutic targets in acute lung injury as well as fibrotic and degenerative diseases. Far from being passive and quiescent, pericytes and resident fibroblasts are busily sensing and responding, through diverse mechanisms, to changes in lung health and function.

Figure 1

Tissue architecture and mesenchymal lineages in the lung. A: Electron microscopy photomicrographs of normal mouse lung showing fibroblast processes abutting epithelium and pericyte processes attached to endothelium and within a loose capillary basement membrane. Fluorescence images of inflated lung (B) and scheme (C) showing FoxD1 lineage pericytes (red) and cells producing collagen (Col) 1 (green). Note extensive mesenchymal cell populations in normal lung. In disease, both pericyte-derived cells and Col1⁺, platelet-derived growth factor receptor-α⁺ resident fibroblast–derived cells contribute to Col1 production in the foci of fibrosis. Scale bars: 1 μm (A); 50 μm (B and C). a, alveolus; c, capillary; cbm, capillary basement membrane; ec, endothelial cell; epi, epithelial cell; f, fibroblast; p, pericyte; rbc, red blood corpuscle.

Figure 2

Model of mesenchymal lineages in development of the lung. Solid lines show the relationships between cell types identified by lineage tracing studies in the embryonic, healthy adult, and injured lung (Table 2). Dashed lines indicate additional hypotheses for the origins of α-smooth muscle actin (α-SMA)⁻ pathogenic fibroblasts in injured lung. The earliest embryonic expression of genes used for tracing are depicted on the left. Note that the timing of inducible tracing also determines which populations will be marked. Col, collagen; E, embryonic day; NG, neural/glial antigen; PDGFR, platelet-derived growth factor receptor.

Figure 3

Collagen (Col) 1 expression distinguishes between immune and matrix-oriented lung fibroblasts. Hung et al characterized the most enriched Kyoto Encyclopaedia of Genes and Genomes gene ontology pathways (www.genome.jp/kegg, last accessed June 2016) in the three FoxD1/Col1 fibroblast subsets in healthy lung. Immune and chemotaxis pathways are more enriched in FoxD1⁺/Col1⁻ cells, whereas matrix, adhesion, and developmental pathways are more strongly engaged in Col1⁺ cells. Top differentially expressed genes playing important roles in inflammation, tissue remodeling, and lung genesis, or degeneration were selected from the complete data set for discussion.