Ferroptosis of selective progenitor cell types during embryogenesis ensures proper organ morphogenesis

Ferroptosis, a type of cell death not associated with apoptosis, is triggered by lipid peroxidation due to an excess of labile iron within cells (1). Although apoptosis plays a part in embryonic development (2), the involvement of ferroptosis in embryogenesis remains unexplored. This study reveals that ferroptosis takes place in the embryonic lung and kidney during mid- and late-gestation stages.

Pro-ferroptotic cells in these tissues comprise Sox9+ distal lung epithelial cells and Flk1+ vascular progenitors in the kidney glomeruli (3).

Through lipidomic analysis, the research indicates that mixed lipid peroxidation serves as the driving force behind ferroptosis. The impact of ferroptosis on the development of these organs is validated by the presence of TfR1, 4-HNE, and TUNEL markers, along with mitochondrial defects, membrane rupture, dead cell remnants, and the identification of a ferroptosis gene signature through single-cell RNA-sequencing (4).

Genetic modifications of Gpx4, an intrinsic protector against ferroptosis, are also examined. The manipulation of Gpx4 affects lung and kidney development, leading to cystic lungs and kidneys when Gpx4 is knocked out or overexpressed through genetic modifications (5). Specifically, conditional deletion of Gpx4 results in hypoplasia of lung epithelia and renal glomeruli, while transgenic overexpression of Gpx4 causes atelectasis with collapsed lung alveoli and hypertrophic glomeruli.

These findings collectively demonstrate that ferroptosis plays a crucial role in regulating lung and kidney morphogenesis by targeting specific progenitor cell populations during gestation (6). The study suggests that the supplementation of iron or polyunsaturated fatty acids during pregnancy may have implications for organogenesis.