FGF Signaling in Lung Development and Disease: Human Versus Mouse

Abstract

Fibroblast growth factor 10 (FGF10) plays an important role in mouse lung development, injury, and repair. It is considered the main morphogen driving lung branching morphogenesis in rodents. While many studies have found FGF10 SNPs associated with COPD and branch variants in COPD smokers, there is no evidence of a causative role for FGF10 or these SNPs in human lung development and pediatric lung diseases. We and others have shown divergent roles for FGF10 in mouse lung development and early human lung development. Herein, we only review the existing literature on FGF signaling in human lung development and pediatric human lung diseases, comparing what is known in mouse lung to that in human lung.

Keywords: FGF signaling; FGF10; development; disease; human lung.

Figure 1

Differences in structure and cellular composition between human and mouse lungs. Cartilage rings (blue) extend into the bronchioles in human lungs but are present only in the trachea and bronchi in mouse. Submucosal glands (green) are limited to the trachea in mouse but are present into the smaller respiratory bronchioles in humans. In mouse, only the trachea and main stem bronchi are lined with pseudostratified epithelium, whereas in humans, all the conducting airways from the trachea to the bronchioles are lined with pseudostratified epithelium. Basal cells (purple) are found deeper into the bronchioles only in humans. The human lung consists of more goblet cells (dark blue) in the proximal epithelium, with Club cells (yellow) mostly restricted to the smaller airways. Conversely, the mouse lung contains more Club cells (yellow) through the trachea and bronchi, with less goblet cells throughout. Neuroendocrine cells (light blue) are present within the bronchioles in clusters in the mouse and isolated or in much smaller clusters throughout the entire epithelial tree in human. Club cells = yellow, Ciliated cells = pink, Basal cells = purple, Goblet cells = dark blue, Neuroendocrine cells = light blue.

Figure 2

Schematic depiction of the differential expression of SOX2, SOX9, ACTA2, and FGF10 between the developing human and mouse lung during the pseudoglandular stage. SOX2/SOX9 double positive progenitor cells are present in the distal epithelial tips of the human lung, whereas only SOX9+ cells are present in the distal tips of the mouse. ACTA2+ smooth muscle cells are found in both human and mouse surrounding the proximal airway, but extend more distally into the human lung and are closely associated with SOX2+ cells only, they are also in human at the bifurcation of the branch tips. In mouse lung, Fgf10 is highly expressed in the mesenchyme adjacent to the epithelial tips and in the smooth muscle cells surrounding the airways; whereas in humans FGF10+ cells are found dispersed throughout the mesenchyme with little expression in the smooth muscle cells.