Preeclampsia-Linked Protease Prostasin Found Essential for Embryonic Blood Cell Maturation

A protease already linked to one of pregnancy’s most feared complications has now been caught playing an unexpected role in the making of blood itself. In a study published in PLOS One, researchers report that mouse embryos lacking the membrane-bound serine protease prostasin, encoded by the gene Prss8, suffer a profound failure of red blood cell maturation that contributes to their death in mid-gestation. The finding ties a gene associated with preeclampsia in humans directly to the embryonic machinery that produces the first red blood cells of life, and suggests that placental pathologies may share roots with defects in fetal blood development.

Prostasin has long interested researchers because of its association with preeclampsia, a gestational hypertension disorder that disrupts the blood supply of the placenta and endangers both mother and fetus. In mice, complete deficiency of Prss8 is lethal by embryonic day 14.5, and the embryos show impaired maturation of the placental labyrinth, the intricate vascular interface where maternal and fetal circulations exchange oxygen and nutrients. What remained unclear was whether the protease acts directly within blood-forming tissues or whether its effects on blood cells are secondary to the failing placenta. The new study, led by Sara Di Carlo, Adrian Salas-Bastos, Olaia Naveiras and Edith Hummler among others, set out to answer that question with a combination of classical developmental biology and single-cell genomics.

The team examined Prss8-deficient embryos at embryonic days 11.5 and 12.5, a critical window when the embryo transitions from relying on primitive red blood cells made in the yolk sac to producing definitive blood lineages that will sustain it for life. At both time points, they found a reduced frequency of circulating primitive erythroid cells and of definitive erythroblasts derived from erythro-myeloid progenitors in three key hematopoietic sites: the yolk sac, the placenta and the fetal liver. This was not a subtle shift. Across the entire network of embryonic blood production, the absence of prostasin thinned out the population of maturing red cells, suggesting the protease supports erythropoiesis at a systemic level rather than in a single niche.

To understand what was going wrong inside the affected cells, the researchers turned to single-cell RNA sequencing, a technique that profiles the gene expression of individual cells and can reveal developmental states that bulk measurements average away. The analysis of primitive erythroid cells from Prss8-deficient embryos revealed two striking transcriptional signatures. First, genes encoding fetal hemoglobin, the oxygen-carrying molecules that primitive red cells depend on, were downregulated. Second, ribosomal genes were upregulated, hinting at an altered translational program or a stress response within the cells. Together, these changes indicate a defective erythroid maturation: the red blood cell precursors were not simply fewer in number, they were failing to progress along their normal differentiation trajectory.

One of the most consequential observations came from asking where prostasin itself is expressed during this process. The answer, according to the study, is nowhere near the cells that need it. Prostasin expression was absent in circulating erythroid cells, which means the protease cannot be acting cell-intrinsically within the red cell lineage. The researchers therefore propose that prostasin regulates primitive erythropoiesis in a cell-extrinsic manner, shaping the environment in which red cells mature rather than the cells themselves. This distinction matters enormously for how the finding is interpreted: prostasin is not a blood cell gene, but a gene whose product in surrounding tissues makes blood cell development possible.

The search for that extrinsic environment led the team to the vasculature. In Prss8-deficient embryos, yolk sac vascular remodeling was impaired, as evidenced by reduced vessel branching and reduced junctions between vessels. The yolk sac is the first hematopoietic and vascular organ of the embryo, and its blood vessels must remodel and expand in lockstep with the growing demand for oxygen transport. When branching fails, the circulatory architecture that delivers oxygen and removes waste is compromised. The authors suggest that this vascular defect likely affects placental vascularization as well, compounding the labyrinth maturation failure already known from earlier work, and contributing to the embryonic demise observed by day 14.5.

This vascular connection is where the study becomes most relevant to human pregnancy. Preeclampsia is fundamentally a disorder of placental blood supply, characterized by inadequate remodeling of maternal spiral arteries and subsequent placental ischemia. The new data show that in mice, loss of prostasin simultaneously disrupts embryonic red cell production and vascular patterning in the yolk sac and placenta. The convergence of these two processes, hematopoiesis and vascular development, in a single protease suggests that Prss8 dysregulation may contribute to placental pathologies through mechanisms that go beyond the classical view of preeclampsia as purely a maternal vascular disorder. A failing fetal blood system and a failing placental circulation may be two faces of the same underlying defect.

Technically, the study’s strength lies in its multi-scale approach. By combining embryo staging at defined gestational days, flow-based quantification of erythroid populations across three organs, and single-cell transcriptomics, the researchers could distinguish between a loss of cells and a loss of maturation within the cells that remain. The downregulation of fetal hemoglobin genes is particularly telling, because primitive erythroid cells are defined by their robust hemoglobin production; a primitive cell that fails to express hemoglobin genes is a cell that has lost its identity. The concurrent upregulation of ribosomal genes may reflect a compensatory attempt to sustain protein synthesis, or an early sign of cellular stress, and disentangling these possibilities will be an important direction for future work.

The cell-extrinsic mechanism also reframes what prostasin does biologically. As a membrane-bound serine protease, prostasin is known to participate in epithelial sodium channel regulation and in the proteolytic processing of extracellular substrates. Its absence from circulating erythroid cells implies that its relevant substrates lie in the vascular and stromal compartments of the yolk sac, placenta and fetal liver. Whether prostasin processes a specific extracellular molecule that signals to erythroid precursors, or whether its vascular effects alone account for the erythroid defects, remains an open question that the study raises but does not fully resolve. The impaired vessel branching and junctions provide a plausible route: a poorly patterned vasculature cannot properly support the niches in which red cells are born and mature.

For now, the findings unveil a novel role for prostasin during developmental erythropoiesis and vascular patterning, and they provide insight into how Prss8 dysregulation may contribute to placental pathologies such as preeclampsia. The work demonstrates that a protease associated with a pregnancy disorder in humans is essential for the embryonic blood system in mice, linking placental health, vascular architecture and red cell maturation in a single genetic axis. As researchers pursue the extracellular substrates and signaling pathways through which prostasin acts, the study opens a path toward understanding whether the same protease that sculpts the embryonic vasculature also safeguards the placental circulation that sustains human pregnancies, and whether its dysregulation could one day be targeted therapeutically in disorders of the placenta.

Subject of Research: The role of the serine protease prostasin in embryonic erythropoiesis and placental vascular development

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

Article References: Di Carlo, S., Salas-Bastos, A., Castelblanco Castelblanco, M., Auberson, M., Wang, D., Rumpler, M., Tournier, M., Staub, O., Sommer, L., Ferreira Lopes, S., Jiménez Sànchez, A., Naveiras, O., & Hummler, E. (2026). Impaired erythroid maturation in murine embryos upon loss of the preeclampsia-associated serine protease prostasin Prostasin loss impairs erythropoiesis. PLOS One, 21(10), e0360958. https://doi.org/10.1371/journal.pone.0360958

Image Credits: AI Generated

DOI: 10.1371/journal.pone.0360958

Keywords: prostasin, Prss8, preeclampsia, erythropoiesis, erythroid maturation, yolk sac, placenta, fetal hemoglobin, single-cell RNA sequencing, vascular remodeling, embryonic development, serine protease