Understanding the developmental pathways pulmonary fibroblasts may follow during alveolar regeneration

Although pulmonary alveolar interstitial fibroblasts are less specialized than their epithelial and endothelial neighbors, they play essential roles during development and in response to lung injury. At birth, they must adapt to the sudden mechanical changes imposed by the onset of respiration and to a higher ambient oxygen concentration. In diseases such as bronchopulmonary dysplasia and interstitial fibrosis, their adaptive responses are overwhelmed leading to compromised gas-exchange function. Thus, although fibroblasts do not directly participate in gas-exchange, they are essential for creating and maintaining an optimal environment at the alveolar epithelial-endothelial interface. This review summarizes new information and concepts about the ontogeny differentiation, and function of alveolar fibroblasts. Alveolar development will be emphasized, because the development of strategies to evoke alveolar repair and regeneration hinges on thoroughly understanding the way that resident fibroblasts populate specific locations in which extracellular matrix must be produced and remodeled. Other recent reviews have described the disruption that diseases cause to the fibroblast niche and so my objective is to illustrate how the unique developmental origins and differentiation pathways could be harnessed favorably to augment certain fibroblast subpopulations and to optimize the conditions for alveolar regeneration.