Platelet‐Derived Growth Factor Receptor‐Alpha‐Expressing Cells Localize to the Alveolar Entry Ring and Have Characteristics of Myofibroblasts During Pulmonary Alveolar Septal Formation

Abstract

Platelet‐derived growth factor‐A and its receptor, platelet‐derived growth factor receptor‐alpha (PDGF‐Rα), are required for formation of the secondary pulmonary alveolar septa in mice. However, it remains unclear how these molecules direct the secondary septation process. We have examined the abundance, location, and the accumulation of alpha‐smooth muscle actin (αSMA), neutral lipid droplets, and elastin in the proximity of PDGF‐Rα‐expressing alveolar cells during postnatal days 4 through 12 in the mouse. PDGF‐Rα‐expressing cells preferentially have characteristics of myofibroblasts and were more likely to contain αSMA than are alveolar cells that do not express PDGF‐Rα. PDGF‐Rα expressing cells were preferentially located in the alveolar entry ring (AER) where αSMA and elastic fibers accumulate. In contrast, PDGF‐Rα expression inversely correlated with neutral lipid accumulation, which was more prominent at the alveolar base, distant from the AER. PDGF‐Rα‐expressing alveolar cells accumulate in the AER where they may promote mechanical stability during respiration. In addition to defining how alveolar septa form, these findings may have implications for the treatment of diseases which involve alveolar effacement such as emphysema and pulmonary fibrosis. Anat Rec, 2008. © 2008 Wiley‐Liss, Inc.

Fibroblasts Expressing PDGF-Receptor-Alpha Diminish During Alveolar Septal Thinning in Mice

“…The pdgf-r␣ expressing LF population increases between P4 and P8 through proliferation (13) and maintains its abundance until at least P12 (19). We have now shown that the pdgfr␣-expressing population diminishes after P12 because of apoptosis and diminished proliferation, resulting in fewer and thinner alveolar walls.…”

“…Our previous studies showed that pdgf-r␣ expressing alveolar cells increased from P4 to P12 (19). To determine whether this increase was influenced by PDGF-R␣ function, we exposed mice to imatinib.…”

“…Lungs were uniformly inflated, fixed, sectioned, and stained for ␣SMA (19). After blocking mouse Fc-receptors with 2.4G2, apoptotic cells were identified using 0.5 g/mL anticleaved poly-ADP ribose polymerase (PARP, clone F21-852; BD Biosciences, Franklin Lakes, NJ) and 7.5 g/mL DyLight 549 anti-mouse IgG1 (Jackson ImmunoResearch, West Grove, PA).…”

The building blocks of mammalian lung development

“…The type 1 cells line the entire alveolar epithelial surface and run adjacent to capillaries in the underlying mesenchyme, providing a minimal barrier for gas exchange. The mesenchyme of the alveoli also contains alveolar smooth muscle cells and stromal fibroblasts, including lipofibroblasts and myofibroblasts, although these cell types may be interconvertible (Kapanci et al, 1974;Lindahl et al, 1997;McGowan et al, 2008;Perl and Gale, 2009). In all regions of the lung, it is difficult to distinguish the different mesenchymal cells, either morphologically or with molecular markers, and there may be additional undescribed subtypes.…”

DA-Raf–dependent inhibition of the Ras-ERK signaling pathway in type 2 alveolar epithelial cells controls alveolar formation

“…Type 1 AECs (AEC1s), which are flat and occupy the large part of alveolar surface, are involved in gas exchange, whereas type 2 AECs (AEC2s), which are small and cuboidal cells, secrete surfactants to lower the surface tension of lungs (1,2). During secondary septation, alveolar myofibroblast (AMYF) precursors expressing platelet-derived growth factor-receptor-α subunit (PDGFRα) are induced by epithelial-derived PDGF-A and differentiate into AMYFs (3)(4)(5)(6). AMYFs expressing contractile α-smooth muscle actin (α-SMA) transiently appear at the tips of the new alveolar septa from postnatal day (P) 5 and deposit extracellular matrix (ECM) proteins, including tropoelastin, collagen, and fibronectin, which provide the driving force for folding up of interalveolar walls (7)(8)(9).…”