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

doi:10.1016/j.isci.2023.106097

Developmental diversity and unique sensitivity to injury of lung endothelial subtypes during postnatal growth

iScience. 2023 Jan 31;26(3):106097. doi: 10.1016/j.isci.2023.106097. eCollection 2023 Mar 17.

Authors

Fabio Zanini¹, Xibing Che^{2

3}, Carsten Knutsen^{2

4}, Min Liu^{2

4}, Nina E Suresh^{2

3}, Racquel Domingo-Gonzalez^{2

4}, Steve H Dou^{2

4}, Daoqin Zhang^{2

4}, Gloria S Pryhuber⁵, Robert C Jones⁶, Stephen R Quake^{6

7

8}, David N Cornfield^{2

3}, Cristina M Alvira^{2

4}

Affiliations

¹ Prince of Wales Clinical School, Lowy Cancer Research Centre, University of New South Wales, Sydney, Kensington, NSW 2052, Australia.
² Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
³ Division of Pulmonary, Asthma and Sleep Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁴ Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁵ Division of Neonatology, Department of Pediatrics, University of Rochester Medical Center, Rochester, NY 14642, USA.
⁶ Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
⁷ Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
⁸ Department of Applied Physics, Stanford University, Stanford, CA 94305, USA.

Abstract

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.

Keywords: Developmental biology; Systems biology; Transcriptomics.

Abstract

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