Department of Surgery, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, United States
Ke Cao
Division of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States
Joanne Chiu
Department of Surgery, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, United States
Hui Chen
Division of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States
Hong-Jun Wang
Division of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States
Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, United States
Brendan H Grubbs
Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, United States
Martin Kolb
Department of Medicine, McMaster University, Hamilton, Canada
Division of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States
Abnormal lung development can cause congenital pulmonary cysts, the mechanisms of which remain largely unknown. Although the cystic lesions are believed to result directly from disrupted airway epithelial cell growth, the extent to which developmental defects in lung mesenchymal cells contribute to abnormal airway epithelial cell growth and subsequent cystic lesions has not been thoroughly examined. In the present study using genetic mouse models, we dissected the roles of bone morphogenetic protein (BMP) receptor 1a (Bmpr1a)-mediated BMP signaling in lung mesenchyme during prenatal lung development and discovered that abrogation of mesenchymal Bmpr1a disrupted normal lung branching morphogenesis, leading to the formation of prenatal pulmonary cystic lesions. Severe deficiency of airway smooth muscle cells and subepithelial elastin fibers were found in the cystic airways of the mesenchymal Bmpr1a knockout lungs. In addition, ectopic mesenchymal expression of BMP ligands and airway epithelial perturbation of the Sox2-Sox9 proximal-distal axis were detected in the mesenchymal Bmpr1a knockout lungs. However, deletion of Smad1/5, two major BMP signaling downstream effectors, from the lung mesenchyme did not phenocopy the cystic abnormalities observed in the mesenchymal Bmpr1a knockout lungs, suggesting that a Smad-independent mechanism contributes to prenatal pulmonary cystic lesions. These findings reveal for the first time the role of mesenchymal BMP signaling in lung development and a potential pathogenic mechanism underlying congenital pulmonary cysts.
