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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.
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This content will become publicly available on March 11, 2026
Advancements and Challenges in Tracheal Epithelium Regeneration: Insights into Tissue Engineering Approaches
BackgroundThe trachea, a vital conduit in the lower airway system, can be affected by various disorders, such as tracheal neoplasms and tracheoesophageal fistulas, that often necessitate reconstruction. While short-segment defects can sometimes be addressed with end-to-end anastomosis, larger defects require tracheal reconstruction, a complex procedure with no universally successful replacement strategy. Tissue engineering offers a promising solution for tracheal repair, particularly focusing on regenerating its epithelium, which plays a critical role in protecting the respiratory system and facilitating mucociliary clearance. However, replicating the complex structure and functionality of the tracheal epithelium remains a significant challenge, with key hurdles including proper cell differentiation, functional mucociliary clearance, and addressing the relative lack of vascular supply to the trachea.SummaryCurrent tissue engineering approaches, including biomaterial scaffolds, decellularized tissues, and scaffold-free methods, have shown varying levels of success, while in vitro air-liquid interface (ALI) cultures have provided valuable insights into epithelial modeling. Despite these advances, translating these findings into effective in vivo applications remains difficult due to challenges such as immune responses, inadequate integration with host tissue, and limited longterm functionality of engineered constructs. Overcoming these barriers requires further refinement of cell sources, scaffold materials and bioactive factors that promote vascularization and sustained epithelial function.Key MessagesThis review evaluates the current strategies and modeling, biomaterial scaffolds, cells, and bioactive factors used in tracheal epithelium regeneration, as well as the methods employed to assess their success through histological, functional, and molecular analyses. While significant progress has been made, the development of a safe, functional, and clinically viable trachealgraft remains elusive, underscoring the need for continued innovation in airway tissue engineering. Future advancements in biomaterial design, stem cell technology, and bioreactor-based tissue maturation hold promise for addressing challenges.
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- Award ID(s):
- 2152254
- PAR ID:
- 10610997
- Publisher / Repository:
- Tissue Engineering-Regenerative Medicine
- Date Published:
- Journal Name:
- Cells Tissues Organs
- ISSN:
- 1422-6405
- Page Range / eLocation ID:
- 1 to 32
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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