Edelstein, S. E. | bioRxiv Science

bioRxiv2026

Epithelial Reprogramming and Transition during Pulmonary Bioengineering

Recent research has emphasized the critical role of cell state transitions in tissue homeostasis. In lung biology, transitional cells are recognized as a feature of tissue-scale processes during both normal physiology and disease. The precise way that transitional cell states emerge and are regulated remains to be determined. Engineered tissues, built in a laboratory through bioengineering approaches, allow detailed study of cellular states that are not commonly found in native biology, and allow opportunities to directly induce and manipulate cellular transitions. The following study explores and characterizes epithelial cell states that emerge via cellular reprogramming in a tissue engineering context. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=172 SRC="FIGDIR/small/701406v1_ufig1.gif" ALT="Figure 1"> View larger version (68K): org.highwire.dtl.DTLVardef@1d456f3org.highwire.dtl.DTLVardef@1989ba5org.highwire.dtl.DTLVardef@127dd7org.highwire.dtl.DTLVardef@3dd7a_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2025

A Tunable Pulmonary Organoid Model Demonstrates Compositionally Driven Epithelial Plasticity and Immune Polarization

Summary/AbstractAberrant epithelial regeneration and immune remodeling are hallmarks of chronic lung diseases such as idiopathic pulmonary fibrosis (IPF), COPD, and post-viral syndromes. Yet how cellular context shapes these trajectories remains unresolved. We present a tunable, primary rat-derived lung organoid model that systematically varies immune, epithelial, and mesenchymal inputs to reveal how composition alone dictates epithelial plasticity and macrophage polarization. Across organoid conditions that varied by relative starting lineage ratios, we observed the spontaneous emergence of disease-relevant transitional cell states, including Sox9+ stressed progenitors, RAS-like intermediates, and hillock-like cells, alongside distinct macrophage activation profiles. In mesenchyme-rich contexts, epithelial-immune-mesenchymal crosstalk appeared to reinforce inflammatory signaling and stabilize transitional persistence, while immune-dominant inputs favored ATI-like repair and squamous remodeling. Hillock-like cells displayed context-specific polarization and expressed immune-regulatory genes, suggesting a role as epithelial orchestrators that help calibrate inflammatory response during regeneration. Connectomic analysis via NICHES revealed that regenerative outcomes were associated with dynamic multicellular signaling networks that integrate stress sensing, immune coordination, and epithelial resilience. This platform provides a tractable system for modeling milieu-specific repair and regenerative mechanisms and could inform therapeutic strategies aimed at redirecting epithelial fate in chronic lung disease.

bioengineering↗