Summary
Millions worldwide suffer from incurable lung diseases, and organ transplantation remains their only hope. However, there has been an absolute shortage of donor lungs and unmet needs for transplantable lung generation composed of tissue-specific mesenchyme, epithelium, and endothelium. Elucidation of lung precursor traits during development can lead to solving this issue. Using lineage-tracing mice, we discovered that gastrulating Foxa2 lineage+ Pdgfrα+ mesendoderm forms the competitive mesenchymal lung niche. We further evidenced that Foxa2+Pdgfrα+ mesendoderm is an evolutionarily-conserved niche during human iPSC-derived lung differentiation. The Fgfr2 gene depletion, specifically in the Foxa2 lineage, showed lung agenesis phenotype. Strikingly, donor iPSCs injection into those blastocysts complemented endodermal and mesodermal defective lung organ niches that efficiently led to the entire lung generation. Together, targeting Foxa2 lineage for lung generation is a novel paradigm, holding a grand promise for future human whole lung generation in large animals using human iPSCs.
Competing Interest Statement
The authors have declared no competing interest.