Airway epithelial cell identity and plasticity are constrained by Sox2 during lung homeostasis, tissue regeneration, and in human disease

Kazushige Shiraishi; Michael P Morley; Dakota L Jones; Gan Zhao; Aaron I Weiner; Maria C Basil; Edward Cantu; Laura T Ferguson; Michele Oyster; Apoorva Babu; Yun Ying; Su Zhou; Shanru Li; Andrew E Vaughan; Edward E Morrisey

doi:10.1038/s41536-023-00344-w

Airway epithelial cell identity and plasticity are constrained by Sox2 during lung homeostasis, tissue regeneration, and in human disease

NPJ Regen Med. 2024 Jan 5;9(1):2. doi: 10.1038/s41536-023-00344-w.

Authors

Kazushige Shiraishi^{1

2}, Michael P Morley^{1

2

3}, Dakota L Jones^{1

2}, Gan Zhao^{2

4

5}, Aaron I Weiner^{2

4

5}, Maria C Basil^{1

2

3}, Edward Cantu^{2

6}, Laura T Ferguson^{1

2}, Michele Oyster¹, Apoorva Babu^{1

2}, Yun Ying^{1

2}, Su Zhou^{1

2}, Shanru Li^{1

2}, Andrew E Vaughan^{2

4

5}, Edward E Morrisey^{7

8

9

10}

Affiliations

¹ Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
² Penn-CHOP Lung Biology Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
³ Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA.
⁴ Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
⁵ Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
⁶ Division of Cardiovascular Surgery, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
⁷ Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. emorrise@pennmedicine.upenn.edu.
⁸ Penn-CHOP Lung Biology Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. emorrise@pennmedicine.upenn.edu.
⁹ Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA. emorrise@pennmedicine.upenn.edu.
¹⁰ Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. emorrise@pennmedicine.upenn.edu.

Abstract

Maintenance of the cellular boundary between airway and alveolar compartments during homeostasis and after injury is essential to prohibit pathological plasticity which can reduce respiratory function. Lung injury and disease can induce either functional alveolar epithelial regeneration or dysplastic formation of keratinized epithelium which does not efficiently contribute to gas exchange. Here we show that Sox2 preserves airway cell identity and prevents fate changes into either functional alveolar tissue or pathological keratinization following lung injury. Loss of Sox2 in airway epithelium leads to a loss of airway epithelial identity with a commensurate gain in alveolar and basal cell identity, in part due to activation of Wnt signaling in secretory cells and increased Trp63 expression in intrapulmonary basal-like progenitors. In idiopathic pulmonary fibrosis, loss of SOX2 expression correlates with increased WNT signaling activity in dysplastic keratinized epithelium. SOX2-deficient dysplastic epithelial cells are also observed in COVID-19 damaged lungs. Thus, Sox2 provides a molecular barrier that suppresses airway epithelial plasticity to prevent acquisition of alveolar or basal cell identity after injury and help guide proper epithelial fate and regeneration.

Abstract

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