Breathing Life into Science: Generating Lung and Airway Epithelial Cells from Human Pluripotent Stem Cells

The ability to generate lung and airway epithelial cells from human pluripotent stem cells (hPSCs) is transforming the landscape of regenerative medicine, respiratory disease modeling, and drug screening. By mimicking the intricate dance of lung development in the lab, researchers are opening doors to personalized therapies, better understanding of diseases like cystic fibrosis and pulmonary fibrosis, and even the possibility of bioengineered lung tissue.

Mimicking the Blueprint of Lung Development

Lung development in the human body is a tightly regulated process orchestrated by signaling pathways like Activin A, BMP (Bone Morphogenetic Protein), FGF (Fibroblast Growth Factor), Wnt, and Retinoic Acid (RA). Researchers are now using this developmental knowledge to replicate these steps in vitro.

The journey begins with the induction of definitive endoderm, the germ layer from which the lungs originate. This is followed by the formation of anterior foregut endoderm, specifically biased toward lung lineage. Finally, through ventralization and patterning, these cells are directed into lung and airway progenitors https://doi.org/10.7554/eLife.05098 .

These multi-step protocols attempt to recreate embryonic development stage-by-stage, a process often referred to as “directed differentiation.”

A Cellular Toolbox: What Can We Generate?

Current protocols have demonstrated success in producing a wide range of lung and airway epithelial cell types, such as:

• Basal cells – stem-like cells responsible for regeneration of airway epithelium
• Goblet cells – mucus-producing cells important for trapping pathogens
• Ciliated cells – responsible for clearing mucus from airways
• Clara (club) cells – involved in detoxification and regeneration
• Type I and Type II alveolar epithelial cells (AT1 and AT2) – crucial for gas exchange and surfactant production

A particularly exciting development is the ability to generate CFTR-expressing airway epithelial cells, a major step forward in studying cystic fibrosis (McCauley et al., 2017).

Hurdles on the Horizon: Challenges and Future Directions

Despite promising strides, challenges remain:

• Purity and Efficiency: Not all cells in a culture differentiate as desired. Often, a heterogeneous population arises, containing off-target endodermal cells like gut or liver progenitors (https://pubmed.ncbi.nlm.nih.gov/25241738/).
• Functional Validation: Simply expressing certain markers isn’t enough. Researchers must confirm that these lab-grown cells function like their in vivo counterparts—that they secrete surfactant, beat cilia, or maintain ion gradients, for example.
• Scalability and Standardization: For real-world applications, differentiation protocols must be scalable and reproducible across labs and cell lines.

To address these gaps, future research is looking into:

• Improved cell sorting or genetic tagging to isolate pure lung progenitors
• Generating or identifying postnatal-like lung stem cells that can give rise to the full repertoire of lung cell types
• Co-culture models that integrate mesenchymal, immune, or vascular cells for better tissue modeling (Konishi et al., 2016)

These innovations could one day lead to the development of bioengineered lung tissues, suitable for transplantation or personalized drug testing platforms.

Final Thoughts

As science continues to unravel the secrets of development, stem cell-based lung models are becoming indispensable tools—not only for understanding respiratory disease, but also for crafting solutions that were once considered science fiction.

From replacing damaged lung tissue to testing drugs on patient-derived cells, hPSC-derived lung cells are poised to reshape respiratory medicine in ways we’re only beginning to imagine.