ORIGINAL RESEARCH article
Front. Cell Dev. Biol.
Sec. Membrane Traffic and Organelle Dynamics
This article is part of the Research TopicExtracellular Vesicles in Regenerative Medicine: From Mechanistic Insights to Clinical TranslationView all articles
Organoid-guided evidence that umbilical cord MSC-derived extracellular vesicles restore alveolar repair in cigarette smoke-induced lung injury
Provisionally accepted
- 1University of Science Malaysia (USM), Penang, Malaysia
- 2Universiti Sains Malaysia, Minden Heights, Malaysia
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Chronic cigarette smoke (CS) disrupts epithelial homeostasis, fuels persistent inflammation, and impairs alveolar repair—hallmarks of COPD with few disease-modifying options. Extracellular vesicles (EVs) from human umbilical cord mesenchymal stem cells (hUC-MSCs) are emerging as cell-free modulators of regeneration, yet their impact on the CS-injured alveolus and alveolar type-2 (AT2) stem/progenitor programs remains unclear. We used a preclinical model of chronic CS exposure coupled with organoid-guided analyses to test whether hUC-MSC-derived EVs can restore epithelial regeneration while tempering injury-associated inflammation and remodeling. Following CS injury, animals received vehicle, hUC-MSCs, or purified hUC-MSC EVs; lungs were evaluated histologically (airway/parenchymal inflammation, emphysema-like change), by Masson’s trichrome (collagen deposition), and functionally using ex vivo epithelial organoids (organoid number/size, architecture, and AT2/AT1 marker balance). Transcriptomic profiling of organoid-derived RNA mapped pathway-level changes. CS induced robust immune-cell infiltration, increased collagen, and abnormal organoid phenotypes consistent with dysregulated progenitor activity. Post-injury EV treatment reduced inflammatory infiltrates and collagen, normalized organoid number and size, and restored AT2/AT1 lineage balance toward naïve patterns. At the molecular level, EVs dampened injury-upregulated circuits (including IL-17, PI3K–AKT–mTOR, MAPK, oxidative-stress and matrix-remodeling signatures) and enriched pathways associated with epithelial homeostasis and barrier integrity. Together, these data position hUC-MSC EVs as precision modulators of the injured alveolar niche that rebalance inflammation and re-engage endogenous regenerative programs. The organoid-guided, multi-scale readouts provide mechanistic insight and a translational rationale for EV-based regenerative therapeutics in smoke-induced lung injury and, by extension, COPD.
Keywords: Alveolar regeneration, Cigarette smoke (CS), extracellular vesicles, Lung organoids, Umbilical cord mesenchymal stem cells
Received: 21 Sep 2025; Accepted: 12 Feb 2026.
Copyright: © 2026 Yahaya, Che Shaffi, Ishtiah and Patar. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Badrul Hisham Yahaya
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