Developmental diversity and unique sensitivity to injury of lung endothelial subtypes during postnatal growth
Fabio Zanini,
Xibing Che,
Carsten Knutsen,
Min Liu,
Nina E. Suresh,
Racquel Domingo-Gonzalez,
Steve H. Dou,
Daoqin Zhang,
Gloria S. Pryhuber,
Robert C. Jones,
Stephen R. Quake,
David N. Cornfield,
Cristina M. Alvira
Affiliations
Fabio Zanini
Prince of Wales Clinical School, Lowy Cancer Research Centre, University of New South Wales, Sydney, Kensington, NSW 2052, Australia
Xibing Che
Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Division of Pulmonary, Asthma and Sleep Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
Carsten Knutsen
Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
Min Liu
Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
Nina E. Suresh
Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Division of Pulmonary, Asthma and Sleep Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
Racquel Domingo-Gonzalez
Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
Steve H. Dou
Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
Daoqin Zhang
Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
Gloria S. Pryhuber
Division of Neonatology, Department of Pediatrics, University of Rochester Medical Center, Rochester, NY 14642, USA
Robert C. Jones
Department of Bioengineering, Stanford University, Stanford, CA 94305, USA
Stephen R. Quake
Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA; Department of Applied Physics, Stanford University, Stanford, CA 94305, USA
David N. Cornfield
Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Division of Pulmonary, Asthma and Sleep Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
Cristina M. Alvira
Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA; Corresponding author
Summary: At birth, the lung is still immature, heightening susceptibility to injury but enhancing regenerative capacity. Angiogenesis drives postnatal lung development. Therefore, we profiled the transcriptional ontogeny and sensitivity to injury of pulmonary endothelial cells (EC) during early postnatal life. Although subtype speciation was evident at birth, immature lung EC exhibited transcriptomes distinct from mature counterparts, which progressed dynamically over time. Gradual, temporal changes in aerocyte capillary EC (CAP2) contrasted with more marked alterations in general capillary EC (CAP1) phenotype, including distinct CAP1 present only in the early alveolar lung expressing Peg3, a paternally imprinted transcription factor. Hyperoxia, an injury that impairs angiogenesis induced both common and unique endothelial gene signatures, dysregulated capillary EC crosstalk, and suppressed CAP1 proliferation while stimulating venous EC proliferation. These data highlight the diversity, transcriptomic evolution, and pleiotropic responses to injury of immature lung EC, possessing broad implications for lung development and injury across the lifespan.
