Impaired erythroid maturation in murine embryos upon loss of the preeclampsia-associated serine protease prostasin Prostasin loss impairs erythropoiesis

In humans, the membrane-bound serine protease prostasin encoded by Prss8 is associated with preeclampsia, a gestational hypertension disorder affecting blood supply of the placenta. Deficiency of Prss8 in mice resulted in embryonic lethality by embryonic day (E) 14.5 and impaired maturation of placental labyrinth. We found in Prss8 -/- embryos at E11.5 and E12.5 a reduced frequency of both circulating primitive and erythro-myeloid progenitor (EMP)-derived definitive erythroblasts in the yolk sac, placenta and fetal liver. Single-cell RNA sequencing analyses revealed a downregulation of fetal hemoglobin genes and an upregulation of ribosomal genes in primitive erythroid cells of Prss8 -/- embryos, indicating a defective erythroid maturation. We suggest that prostasin regulates primitive erythropoiesis in a cell-extrinsic manner, since its expression was absent in circulating erythroid cells. Indeed, the yolk sac vascular remodeling of Prss8 -/- embryos was impaired as evidenced by reduced vessel branching and junctions, likely affecting placenta vascularization and contributing to embryonic demise. Our findings unveil a novel role for prostasin during developmental erythropoiesis and vascular patterning and provide insight into how Prss8 dysregulation may contribute to placental pathologies such as preeclampsia.