Alveologenesis: What Governs Secondary Septa Formation

Abstract

The simplification of alveoli leads to various lung pathologies such as bronchopulmonary dysplasia and emphysema. Deep insight into the process of emergence of the secondary septa during development and regeneration after pneumonectomy, and into the contribution of the drivers of alveologenesis and neo-alveolarization is required in an efficient search for therapeutic approaches. In this review, we describe the formation of the gas exchange units of the lung as a multifactorial process, which includes changes in the actomyosin cytoskeleton of alveocytes and myofibroblasts, elastogenesis, retinoic acid signaling, and the contribution of alveolar mesenchymal cells in secondary septation. Knowledge of the mechanistic context of alveologenesis remains incomplete. The characterization of the mechanisms that govern the emergence and depletion of αSMA will allow for an understanding of how the niche of fibroblasts is changing. Taking into account the intense studies that have been performed on the pool of lung mesenchymal cells, we present data on the typing of interstitial fibroblasts and their role in the formation and maintenance of alveoli. On the whole, when identifying cell subpopulations in lung mesenchyme, one has to consider the developmental context, the changing cellular functions, and the lability of gene signatures.

Keywords: alveolar interstitial resident fibroblasts; alveologenesis; elastin; extracellular matrix; lipofibroblasts; lung regeneration; myofibroblasts; pneumonectomy; retinoic acid signaling; secondary septa.

Figure 1

Lung development. Development of the lung as a whole and its proximal parts is shown in blue. Development of the distal lung and alveologenesis is shown in purple. E, embryonic day; P, postnatal day. The timescale, shown in weeks, refers to the stages of human lung development.

Figure 2

Alveolar secondary septa. Classical alveologenesis. Immature, thick secondary septa. Double capillary network (A). Continued alveologenesis. Mature, thin secondary septa. Single capillary network (B). Redrawn from [23,26].

Figure 3

Cross-section of the alveola with a view of the secondary septa. αSMA fibers, marked in pink, and closely related elastin matrices, marked in purple, are expressed in an organized network, mimicking a “fishnet” pattern in the alveolar region. The alveolar epithelium is marked in blue. The black dotted line indicates the entrance alveolar ring (AER) (A). Septal ridges in 2D look like an assembly of αSMA fibers on the tips of secondary septa (asterisks) (B). The gray line imitates the cutting line. Redrawn from [39].