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

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Abstract 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. Mice deficient in Prss8 resulted in the death of embryos at embryonic day (E) 14.5 and it was characterized by impaired placental labyrinth maturation and vascularization. A pale phenotype was observed in these embryos, suggesting ineffective erythropoiesis. Thus, in this study we analyzed this phenotype further in Prss8 -/- embryos at E11.5 and E12.5. We found a reduced number of fetal erythroblasts in placenta, yolk sac and fetal liver of Prss8 -/- embryos, while the reticulocyte number was increased, suggesting a defective terminal erythroid differentiation. Further, single-cell RNA sequencing (scRNA-seq) analyses of aorta-gonad-mesonephros (AGM) revealed an upregulation of several ribosomal genes associated with Diamond-Blackfan anemia in erythroid cells of Prss8 -/- (KO) embryos. These cells showed a lower capacity to maturate into erythrocytes in vivo and in vitro, despite hematopoietic cells (HSCs) being produced normally. We suggested prostasin influenced erythropoiesis in a cell-extrinsic manner, since Prss8 expression was not detected in erythroid cells but highly expressed in ectoderm-like cells within the AGM. Congruently, while yolk sac-derived cells displayed no erythroid maturation defect in vitro , the yolk sac vascular remodeling in KO embryos was impaired as evidenced by reduced secondary branching likely as a consequence of the reduced blood flow. Our findings unveiled a novel role for this serine protease in terminal maturation of erythrocytes in the fetal liver and open new research avenues for understanding the physiological mechanism of prostasin and its pathological implications. Key Points Prss8 deficiency causes transcriptional changes in erythroid progenitor cells in the AGM leading to impaired embryonic erythropoiesis Overexpression of Rpl and Rps genes by erythroid cells lacking Prss8 leads to defective erythropoiesis and embryonic lethality