ALVEOGENESIS FAILURE IN PDGF-A-DEFICIENT MICE IS COUPLED TO LACK OF DISTAL SPREADING OF ALVEOLAR SMOOTH-MUSCLE CELL PROGENITORS DURING LUNGDEVELOPMENT

PDGF-A(-/-) mice lack lung alveolar smooth muscle cells (SMC), exhibit reduced deposition of elastin fibres in the lung parenchyma, and deve lop lung emphysema due to complete failure of alveogenesis, We have ma pped the expression of PDGF-A, PDGF receptor-alpha, tropoelastin, smoo th muscle alpha-actin and desmin in developing lungs from wild type an d PDGF-A(-/-) mice of pre- and postnatal ages in order to get insight into the mechanisms of PDGF-A-induced alveolar SMC formation and elast in deposition, PDGF-A was expressed by developing lung epithelium. Clu sters of PDGF-R alpha-positive (PDGF-R alpha(+)) mesenchymal cells occ urred at the distal epithelial branches until embryonic day (E) 15.5. Between E16.5 and E17.5, PDGF-R alpha(+) cells multiplied and spread t o acquire positions as solitary cells in the terminal sac walls, where they remained until the onset of alveogenesis. In PDGF-A(-/-) lungs P DGF-R alpha(+) cells failed to multiply and spread and instead remaine d in prospective bronchiolar walls, Three phases of tropoelastin expre ssion were seen in the developing lung, each phase characterized by a distinct pattern of expression, The third phase, tropoelastin expressi on by developing alveolar SMC in conjunction with alveogenesis, was sp ecifically and completely absent in PDGF-A(-/-) lungs, We propose that lung PDGF-R alpha(+) cells are progenitors of the tropoelastin-positi ve alveolar SMC, We also propose that postnatal alveogenesis failure i n PDGF-A(-/-) mice is due to a prenatal block in the distal spreading of PDGF-R alpha(+) cells along the tubular lung epithelium during the canalicular stage of lung development.