Alveogenesis failure in PDGF-A-deficient mice is coupled to lack of distal spreading of alveolar smooth muscle cell progenitors during lung development

Abstract

PDGF-A(−/−) mice lack lung alveolar smooth muscle cells (SMC), exhibit reduced deposition of elastin fibres in the lung parenchyma, and develop lung emphysema due to complete failure of alveogenesis. We have mapped the expression of PDGF-A, PDGF receptor-alpha, tropoelastin, smooth muscle alpha-actin and desmin in developing lungs from wild type and PDGF-A(−/−) mice of pre- and postnatal ages in order to get insight into the mechanisms of PDGF-A-induced alveolar SMC formation and elastin deposition. PDGF-A was expressed by developing lung epithelium. Clusters of PDGF-Ralpha-positive (PDGF-Ralpha+) mesenchymal cells occurred at the distal epithelial branches until embryonic day (E) 15.5. Between E16.5 and E17.5, PDGF-Ralpha+ cells multiplied and spread to acquire positions as solitary cells in the terminal sac walls, where they remained until the onset of alveogenesis. In PDGF-A(−/−) lungs PDGF-Ralpha+ cells failed to multiply and spread and instead remained in prospective bronchiolar walls. Three phases of tropoelastin expression were seen in the developing lung, each phase characterized by a distinct pattern of expression. The third phase, tropoelastin expression by developing alveolar SMC in conjunction with alveogenesis, was specifically and completely absent in PDGF-A(−/−) lungs. We propose that lung PDGF-Ralpha+ cells are progenitors of the tropoelastin-positive alveolar SMC. We also propose that postnatal alveogenesis failure in PDGF-A(−/−) mice is due to a prenatal block in the distal spreading of PDGF-Ralpha+ cells along the tubular lung epithelium during the canalicular stage of lung development.

Relationship between impaired BMP signalling and clinical risk factors at early-stage vascular injury in the preterm infant

“…Successfully anchoring impaired BMPR2 signalling in the context of BPD characteristic lung structural changes, we established its interdependency with PDGF-Rα expression, that is, known to hold critical functions in alveolar septation, extracellular matrix formation and vascular development 19 20 30 31. The intertwined regulation of both pathways supports the relation of lung fibrosis and vascular pathology indicated by previous studies,32 33 aggravated by the proliferation of apoptosis-resistant ECs in the presence of impaired BMPR2 signalling34 and the subsequent exposure of subendothelial cells to growth factors and chemokines due to decreased EC barrier function 35.…”

Biomaterials for Bioprinting Microvasculature

“…As a result, the activation of PDGFRs is highly involved in many types of organogenesis, including vascular development. In addition to supporting the fundamental functions of ECs (e.g., survival and proliferation), PDGFs also play critical roles in the function of multiple supporting cell types, such as pericytes and SMCs . Specifically, PDGF-B targets PDGFR-β as a paracrine signaling mechanism between ECs and perivascular cells .…”

Developmental Pathways Underlying Lung Development and Congenital Lung Disorders

“…For instance, platelet-derived growth factor A chain (PDGF-A) and its receptor (PDGFRα/β) have been shown to play key roles in myofibroblast differentiation and production of elastin [ 91 ]. In PDGF-A deficient mice, alveolarization failed to occur and exhibited reduced elastic fibers deposition, showing that the appearance of elastin and alveolar crests are closely linked [ 92 ]. Bundles of elastin laid down by myofibroblasts restrain the differentiating alveolar cells that are expanding into sacculi as development proceeds.…”