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

Abstract

Ferroptosis, a form of non-apoptotic cell death, is induced by lipid peroxidation resulting from an intracellular accumulation of labile iron (1). While apoptosis is involved in embryonic development (2), the role of ferroptosis in embryogenesis is unknown. Here, we report that the ferroptosis process occurs in the embryonic lung and kidney at mid- and late-gestation. In these tissues, pro-ferroptotic cells include subpopulations of the Sox9+ distal lung epithelial cells and the Flk1+ vascular progenitors in the kidney glomeruli. Lipidomic analysis reveals mixed lipid peroxidation as the driver for ferroptosis. The role of ferroptosis in the morphogenesis of these organs was confirmed by triple positivity of TfR1, 4-HNE and TUNEL, mitochondrial defects, cell membrane breakage, dead cell remnants, single-cell RNA-sequencing of a ferroptosis gene signature. Genetic manipulation of Gpx4, an endogenous inhibitor of ferroptosis. Further, genetic knockout or transgenic overexpression of Gpx4 affects lung and kidney development and results in cystic lungs and kidneys. Notably, conditional deletion Gpx4 results in hypoplasia of the lung epithelia and of the renal glomeruli, while transgenic overexpression of Gpx4 resulted in atelectasis with collapsed lung alveoli and hypertrophic glomeruli. Together, these findings show that ferroptosis regulates lung and kidney morphogenesis by acting in key progenitor cell populations during gestation. Supplementation of iron or polyunsaturated fatty acid during pregnancy has implications for organogenesis.