Stromal Regulation of Lung Regeneration and Repair

The lung comprises a diverse array of specialized cell types that together form complex intercellular communication networks necessary for its proper development and function. The epithelium and the mesenchyme comprise the two major cellular compartments of the lung, where reciprocal signalling is key to the development and maintenance of the functional architecture of the organ. During development, signals from the mesenchyme drive epithelial proliferation, differentiation, and morphogenetic patterning to generate branching airways and alveoli [1, 2]. These interactions are mediated by a myriad of growth factors that are precisely regulated in their temporal and spatial expression to direct the differentiation of specialized cells and their organization into a complex three-dimensional (3D) structure that facilitates respiration and protection against inhaled pathogens. The relationship between alveolar epithelium and pulmonary capillaries permits for gas-exchange, while the airway epithelium plays a major role in microbial defence, immune regulation, mucociliary clearance of pathogens and toxins; and as a physical barrier to exogenous particles in the air we breathe [3]. Mesenchymal progenitor cells differentiate into various lineages to create cartilage rings, providing structural support in the trachea, and contractile smooth muscle cells, fibroblasts, pericytes, and myofibroblasts throughout the lung [4, 5]. There is also some evidence to suggest that a subset of mesenchymal cells are capable of differentiating into endothelial cells in the lung [5, 6]. The mesenchymal compartment is also responsible for the elaboration of extracellular matrix proteins and cytokines that in addition to epithelial-mesenchymal interactions provide the permissive or restrictive cues during development.