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

Differentiation syndrome occurs when ATRA and ATO, which work by forcing the immature leukemic cells of APL to mature and eventually die, trigger a violent inflammatory reaction in the process. Patients can develop fever, fluid accumulation in the lungs, low blood pressure, and kidney failure. In severe cases, the syndrome can be fatal. Despite decades of clinical experience, the biological mechanisms underlying the condition have remained poorly understood, and doctors currently have no reliable way to predict which patients will develop it. The new research, led by Giulia Falconi, Luca Guarnera, and Maria Teresa Voso of the University of Rome Tor Vergata, together with colleagues across Italy, set out to change that by examining the clinical, molecular, and cellular fingerprints of the syndrome.

The team analyzed two independent groups of APL patients. The first was a real-life cohort of 34 patients treated at multiple Italian centers, reflecting the diversity of everyday clinical practice. The second comprised 18 patients enrolled in the landmark APL0406 clinical trial, the study that established the ATRA-ATO combination as the standard of care. From each patient, the researchers collected blood samples at baseline and at sequential time points during treatment, allowing them to track molecular changes as therapy unfolded. Crucially, the analysis included both patients who developed differentiation syndrome and those who did not, providing a natural comparison group.

The most striking clinical finding concerned transfusions. Patients who went on to develop differentiation syndrome required a median of nine units of red blood cells during the induction phase of treatment, compared with just three units in patients who did not develop the syndrome—a difference that was highly statistically significant. Even after adjusting for other clinical variables in a multivariable analysis, the transfusion burden retained its independent association with the syndrome. In other words, patients whose disease demanded more blood support early in treatment were markedly more likely to experience the complication later on.

Why would transfusion requirements track so closely with differentiation syndrome? The answer, the researchers suggest, lies in the biology of erythroid maturation—the process by which red blood cell precursors develop into mature cells. When the team performed RNA sequencing on the patients’ blood samples, they identified 93 genes that were differentially expressed in patients who developed the syndrome. When these gene signatures were mapped onto known biological pathways, they showed striking enrichment for processes related to hematopoietic stem cell differentiation and erythroid maturation. This suggests that the same differentiation programs that ATRA and ATO deliberately activate in leukemic cells may also be perturbing normal blood cell development, particularly the red cell lineage, in susceptible patients.

The molecular data were complemented by measurements of inflammatory signaling molecules. Cytokine profiling of the blood samples revealed elevated levels of interleukin-6, a potent inflammatory messenger, with a trend toward even higher concentrations at the moment the syndrome declared itself. Interleukin-6 is a well-known driver of systemic inflammation and has been implicated in cytokine release syndromes seen with other cancer therapies, including CAR-T cell treatment. Its presence here reinforces the picture of differentiation syndrome as an inflammatory storm, one that unfolds in a molecular environment already primed by disordered blood cell maturation.

But the study did not stop at the leukemic cells themselves. One of its most provocative contributions concerns the endothelium—the delicate layer of cells that lines blood vessels and controls what passes between the bloodstream and surrounding tissues. The researchers grew human pulmonary microvascular endothelial cells, or HPMECs, in the laboratory and exposed them to ATRA and ATO. The drugs induced marked morphological changes in these cells and significantly increased their permeability, allowing fluid and molecules to leak across the endothelial barrier. This laboratory phenomenon closely mirrors the capillary leak that characterizes differentiation syndrome in patients, in which fluid escapes from blood vessels into the lungs and other organs, causing potentially deadly swelling and respiratory distress.

Encouragingly, the researchers found a way to blunt this endothelial damage. When dexamethasone, a corticosteroid commonly used to prevent and treat differentiation syndrome, was added to the cell cultures alongside ATRA and ATO, the increased permeability was significantly attenuated. The finding provides a mechanistic explanation for a clinical practice that has existed for years: steroids work, at least in part, by stabilizing the endothelial barrier against the leak-inducing effects of the leukemia drugs. It also suggests that the laboratory model could be used to test other protective agents in the future.

Taken together, the results support a new model of differentiation syndrome as a three-part process. First, erythroid dysregulation—the same maturation programs triggered in leukemic cells—disrupts normal red cell development, driving the anemia that necessitates transfusions. Second, ATRA and ATO directly injure the endothelial lining of blood vessels, creating a capillary leak phenotype. Third, an inflammatory environment rich in interleukin-6 amplifies the damage. Each element feeds the others, and the transfusion burden emerges as a visible downstream marker of the earliest, hidden phase of the cascade.

The clinical implications could be significant. Red blood cell transfusion counts are recorded routinely for every APL patient, making them an early, inexpensive, and universally accessible biomarker. Patients requiring frequent transfusions during induction could be flagged for closer monitoring, earlier steroid intervention, or enrollment in prospective studies of preventive strategies. The researchers caution that their findings, while compelling, come from a combined cohort of 52 patients, and validation in larger, independent populations will be essential before transfusion burden is adopted into formal risk stratification. Still, in a complication that has long defied prediction, the idea that a number already written in every patient’s chart might reveal who is at highest risk is a rare and welcome piece of good news—one that could help make the cure for acute promyelocytic leukemia not just effective, but safer.

Subject of Research: Differentiation syndrome pathogenesis in acute promyelocytic leukemia

Article Title: Transcriptomic profile and endothelial changes during differentiation syndrome in acute promyelocytic leukemia

Article References: Falconi, G., Guarnera, L., Lazzaroni, F., Galossi, E., Ottone, T., Attardi, E., Piazza, R., Lumia, E., Silvestrini, G., Travaglini, S., Divona, M., Fabiani, E., Curti, A., Martini, V., Mazzone, C., La Barbera, E. O., Sica, S., Mannelli, F., Gurnari, C., … Voso, M. T. (2026). Transcriptomic profile and endothelial changes during differentiation syndrome in acute promyelocytic leukemia. Annals of Hematology. https://doi.org/10.1007/s00277-026-07180-0

Image Credits: AI Generated

DOI: 10.1007/s00277-026-07180-0

Keywords: acute promyelocytic leukemia, differentiation syndrome, all-trans retinoic acid, arsenic trioxide, transcriptomics, endothelial permeability, interleukin-6, red blood cell transfusion, erythroid maturation, dexamethasone, biomarker, hematology