Rational engineering of lung alveolar epithelium

Katherine L Leiby; Yifan Yuan; Ronald Ng; Micha Sam Brickman Raredon; Taylor S Adams; Pavlina Baevova; Allison M Greaney; Karen K Hirschi; Stuart G Campbell; Naftali Kaminski; Erica L Herzog; Laura E Niklason

doi:10.1038/s41536-023-00295-2

Rational engineering of lung alveolar epithelium

NPJ Regen Med. 2023 Apr 28;8(1):22. doi: 10.1038/s41536-023-00295-2.

Authors

Katherine L Leiby^{1

2}, Yifan Yuan³, Ronald Ng¹, Micha Sam Brickman Raredon^{1

2}, Taylor S Adams⁴, Pavlina Baevova³, Allison M Greaney¹, Karen K Hirschi^{5

6

7

8}, Stuart G Campbell^{1

9}, Naftali Kaminski⁴, Erica L Herzog⁴, Laura E Niklason^{10

11}

Affiliations

¹ Department of Biomedical Engineering, Yale University, New Haven, CT, USA.
² Yale School of Medicine, New Haven, CT, USA.
³ Department of Anesthesiology, Yale School of Medicine, New Haven, CT, USA.
⁴ Department of Internal Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, CT, USA.
⁵ Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
⁶ Yale Cardiovascular Research Center, Yale School of Medicine, New Haven, CT, USA.
⁷ Department of Cell Biology, University of Virginia, Charlottesville, VA, USA.
⁸ Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA.
⁹ Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, USA.
¹⁰ Department of Biomedical Engineering, Yale University, New Haven, CT, USA. [email protected].
¹¹ Department of Anesthesiology, Yale School of Medicine, New Haven, CT, USA. [email protected].

Abstract

Engineered whole lungs may one day expand therapeutic options for patients with end-stage lung disease. However, the feasibility of ex vivo lung regeneration remains limited by the inability to recapitulate mature, functional alveolar epithelium. Here, we modulate multimodal components of the alveolar epithelial type 2 cell (AEC2) niche in decellularized lung scaffolds in order to guide AEC2 behavior for epithelial regeneration. First, endothelial cells coordinate with fibroblasts, in the presence of soluble growth and maturation factors, to promote alveolar scaffold population with surfactant-secreting AEC2s. Subsequent withdrawal of Wnt and FGF agonism synergizes with tidal-magnitude mechanical strain to induce the differentiation of AEC2s to squamous type 1 AECs (AEC1s) in cultured alveoli, in situ. These results outline a rational strategy to engineer an epithelium of AEC2s and AEC1s contained within epithelial-mesenchymal-endothelial alveolar-like units, and highlight the critical interplay amongst cellular, biochemical, and mechanical niche cues within the reconstituting alveolus.

Abstract

Grants and funding