Pluripotent-Derived Airway Progenitors Model Lung Fibrosis

In a groundbreaking advance that promises to reshape our understanding of lung diseases and accelerate the path toward effective treatments, researchers have successfully engineered human respiratory airway progenitors from pluripotent stem cells, creating an unprecedented in vitro model that mirrors the human distal respiratory airway cell populations implicated in severe lung disorders such as idiopathic pulmonary fibrosis (IPF). This innovation addresses a critical gap in pulmonary research: the absence of these specialized cells in rodent models, which has long impeded translational studies aimed at deciphering the mechanisms underlying human-specific lung injury and fibrosis.At the heart of this breakthrough are induced respiratory airway progenitors (iRAPs), expandable spherical cell structures derived from human pluripotent stem cells (hPS cells).

These iRAPs consist predominantly—up to 98%—of cell types characteristic of the terminal and respiratory bronchioles (RA/TRBs), the delicate distal regions of the lung where gas exchange occurs and where pathological remodeling in diseases such as IPF takes hold. The sheer scalability of this system is remarkable: a single hPS cell can be propagated to generate on the order of ten billion iRAP cells, providing a vast and renewable resource for experimentation.The scientific team achieved more than just the generation of progenitor cells; they meticulously guided iRAPs through developmental stages that mimic in vivo progression.



By steering the differentiation process towards transitional type 2 alveolar epithelial (AT2) cells and further into mature type 1 alveolar epithelial (AT1) cells, they succeeded in obtaining a highly purified population of mature AT1 cells with an impressive 95% purity. These AT1 cells are essential for forming the thin alveolar lining critical for efficient gas exchange and are notoriously difficult to obtain and study, especially in human contexts.What’s particularly compelling about this model is its ability to recapitulate disease phenotypes associated with genetic mutations.

By introducing deletions in the Heřmanský–Pudlák Syndrome 1 (HPS1) gene—a mutation responsible for a form of pulmonary fibrosis in humans—the iRAP-derived cells exhibited aberrant differentiation patterns and participated in the recruitment of profibrotic fibroblasts. This cellular dysfunction mirrors pathological hallmarks observed in patient lungs affected by IPF, firmly establishing a causal link between intrinsic defects in RA/TRB-associated alveolar progenitors and fibrotic lung disease.The implications here are profound.

Existing animal models, primarily rodents, lack these specific distal airway cell types, limiting their utility for studying IPF and related disorders. By providing a human cell-based platform that faithfully reproduces key pathological features of pulmonary fibrosis, iRAPs open the door to mechanistic investigations previously unattainable, allowing scientists to explore disease progression at the cellular and molecular levels within a human genetic context.Furthermore, iRAPs serve as an invaluable tool for drug discovery and therapeutic validation.

Pharmaceutical pipelines targeting fibrosis have been hampered by the lack of reliable in vitro systems that recapitulate the complexity of human lung cell populations and their interactions with fibrogenic cell types. The scalability and fidelity of this stem cell-derived model promise to accelerate the screening of candidate compounds, elucidate drug mechanisms, and reduce the attrition rates common in clinical development.From a technical perspective, the derivation of iRAPs involves carefully orchestrated culture conditions that mimic developmental cues in the respiratory tract.

The process promotes the expansion of progenitor cells expressing markers consistent with RA/TRB identities, enabling their selective amplification. Successive differentiation is then induced through signaling pathways known to regulate alveolar epithelial lineage commitment, culminating in the generation of mature alveolar type 1 cells. This stepwise protocol not only recapitulates human lung development but also facilitates controlled manipulation and investigation of the cells at defined stages.

The study also sheds light on the pathobiology of the HPS1 mutation, broadly implicating RA/TRB progenitor dysfunction as a central driver in fibrosis onset. By modeling the mutation in a human cellular context, the researchers demonstrated how mutant iRAPs fail to properly differentiate and instead engage in pathological crosstalk with fibroblasts, promoting extracellular matrix deposition and tissue scarring reminiscent of what clinicians observe in end-stage IPF. This insight underscores the potential of targeted interventions aimed at correcting progenitor cell dysfunction to halt or reverse fibrotic remodeling.

Beyond IPF and HPS1-related fibrosis, this platform may have broader applications for studying other distal airway diseases, including chronic obstructive pulmonary disease (COPD), bronchiolitis obliterans, and even viral infections that target alveolar epithelia. The ability to generate homogeneous populations of human lung cells with defined distal airway identities is an essential step towards personalized medicine approaches, where patient-specific hiPS (human induced pluripotent stem) cells could be directed through this lineage to model individual disease susceptibilities and drug responses.The research highlights the importance of human-specific biology in disease modeling.

Rodents have served as invaluable models in pulmonary research but fall short in replicating certain human lung structures and cellular compositions—especially in the distal zones. This novel human iRAP approach circumvents those limitations, providing a more physiologically relevant context for experimental interrogation while reducing reliance on animal models.Moreover, the scalability of the system ensures that high-throughput studies are feasible, addressing a long-standing bottleneck in respiratory research.

The generation of 10^10 cells from a single pluripotent stem cell unlocks the potential for large-scale screens that integrate genomics, transcriptomics, and pharmacological testing under consistent and reproducible conditions.While the study establishes a robust foundation, future research will undoubtedly explore further refinements. Potential avenues include integrating iRAPs within complex lung organoid systems, adding immune cell components, and exploring extracellular matrix interactions to better mimic the in vivo microenvironment.

Such enhancements would provide even richer insights into disease mechanisms and therapeutic targets.Overall, the creation of iRAPs represents a paradigm shift in pulmonary biology. By combining stem cell technology with advanced differentiation protocols and genetic manipulation, scientists now have the tools to dissect distal airway pathologies in unprecedented detail.

The convergence of these technologies heralds a new era of lung disease research that promises to unravel the mysteries of fibrotic progression and inspire novel treatment strategies that can ultimately improve patient outcomes.In summary, the derivation of human respiratory airway progenitors from pluripotent stem cells delivers a scalable and highly faithful platform for modeling alveolar epithelial cell development and disease. The system’s ability to replicate key features of pulmonary fibrosis, particularly those driven by HPS1 mutations, underscores its transformative potential for understanding and combating lethal lung diseases.

As this technology matures, it will undoubtedly become central to global efforts aimed at halting the scourge of IPF and related conditions.—Subject of Research:Human respiratory airway progenitors derived from pluripotent stem cells modeling alveolar epithelial differentiation and pulmonary fibrosis.Article Title:Human respiratory airway progenitors derived from pluripotent cells generate alveolar epithelial cells and model pulmonary fibrosis.

Article References:Pezet, M.G., Torres, J.

A., Thimraj, T.A.

et al. Human respiratory airway progenitors derived from pluripotent cells generate alveolar epithelial cells and model pulmonary fibrosis. Nat Biotechnol (2025).

https://doi.org/10.1038/s41587-025-02569-0Image Credits: AI GeneratedTags: airway progenitor cell modelinghuman respiratory cell populationsidiopathic pulmonary fibrosis studyin vitro lung fibrosis modelsinduced respiratory airway progenitorsinnovative therapies for lung disorderslung disease treatment advancementsmechanisms of lung injurypluripotent stem cell researchpulmonary research breakthroughsscalable cell culture systemstranslational studies in pulmonologySEO Powered Content & PR Distribution.

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Source: https://bioengineer.org/pluripotent-derived-airway-progenitors-model-lung-fibrosis/.