Rational engineering of lung alveolar epithelium

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.

Leveraging mechanobiology and biophysical cues in lung organoids for studying lung development and disease

“…Another natural scaffold for lung epithelium culture consists in the decellularization of the whole lungs preserving its original acellular extracellular matrix (Gilbert et al, 2006;Tommasini et al, 2023) (Figure 2A). Recellularization of the decellularized lungs using lung progenitors derived from human IPSCs have shown successful expansion and alveolar specification of AT2 progenitors (Gilpin et al, 2014;Leiby et al, 2023). Of note, the seeding of human lung organoids on the decellularized lung airway showed minimal or no club cell and goblet cell differentiation (Dye et al, 2015).…”

“…It was found that mechanical stretch alone is unable to affect AT1 differentiation when high levels of Wnt and FGF agonists are present. However, a Wntand FGF-low environment synergizes with tidal-level mechanical strain to promote AT2 differentiation to AT1s within the engineered lung tissues (Leiby et al, 2023). Although challenging, in the future, the combination of biophysical and biochemical cues at different stages in culturing lung organoids should be performed and may be crucial to further promote their maturity.…”

ERK1/2-CEBPB Axis-Regulated hBD1 Enhances Anti-Tuberculosis Capacity in Alveolar Type II Epithelial Cells

“…Among the single-layered flat epithelium that constitutes the alveolar wall, type II alveolar epithelial cells (AEC-II) account for 14-16% of the total alveolar epithelial cells [4]. AEC-II cells possess stemness and can proliferate to form new AEC-II cells, as well as differentiate into type I alveolar epithelial cells (AEC-I) to repair the damaged alveolar epithelial barrier caused by Mtb infection [5]. AEC-II cells perform various anti-infective immune functions in the alveoli.…”