Tun, E. T. | bioRxiv Science

bioRxiv2026

TNFα drives platelet hyperreactivity and thromboinflammation through regulation of hematopoietic stem and progenitor cells.

TNF is the primary age-related cytokine responsible for hyperreactive platelet formation. In mouse models, increased TNF induced abnormal megakaryocyte development and platelet activity. Here, we extend these findings to demonstrate that TNF drives this thrombotic phenotype through expansion of the hematopoietic stem and progenitor cell (HSPCs) compartment. Using HSPC-specific TNF receptor labeling and single cell RNA sequencing, we found that TNF receptors are absent from megakaryocytes and their progenitors (MkPs) indicating that TNF does not directly act on these cells. Chronic TNF exposure expanded HSPCs in the bone marrow and extramedullary tissues - and these expanded HSPCs retained functional repopulation capacity. Using species-specificity TNF receptor activation, we further demonstrate that TNFR1 signaling is sufficient to induce platelet hyperreactivity independent of HSPC expansion. Unlike emergency hematopoiesis, chronic TNF promoted megakaryopoiesis through the canonical hematopoietic hierarchy as demonstrated by lineage-tracing studies. Mechanistically, chronic TNF induced a distinct transcriptional program in single cell RNA sequencing of HSPCs and megakaryocytes. Together, these findings establish that chronic TNF promotes hyperreactive platelet formation not through direct effects on megakaryocytes or MkPs but by expanding and transcriptionally reprogramming HSPCs, thereby imprinting a TNF dependent program that persists through megakaryopoiesis and ultimately produces hyperreactive platelets.

cell biology↗

bioRxiv2025

Neonatal Platelets Differentiate Monocytes to a Myeloid Derived Suppressor Cell Phenotype

Adult platelets are relatively enriched in immune related molecules compared to neonatal platelets, but neonatal platelets express some growth factors and enzymes at comparatively higher levels. This makes a prediction of platelet-immune cell interaction outcomes in neonates a challenge, as they are likely dependent on the cell type and tissue environment at the time of injury or infection. Our past studies revealed that the transfusion of adult but not neonatal platelets into thrombocytopenic neonatal mice led to an acute increase in monocyte trafficking. We have now found that neonatal, but not adult platelets, induce monocytes to a Myeloid Derived Suppressor Cell (MDSC) phenotype, typified by increased PD-L1, that limits T-cell activation in vitro and in vivo. Monocytes prior incubated with neonatal, but not adult platelets, or platelet releasates, limited T-cell activation in vitro. Using an in vivo asthma-like model we also found that the treatment of mice with monocytes prior incubated with neonatal platelet releasates limited T-cell activation in a asthma-like model. Platelet-driven effects were dependent on neonatal platelets producing more PGE2 that signaled through monocyte EP4. These studies indicate that neonatal platelets have immune limiting roles in the post-natal period by indirectly limiting T-cell responses, perhaps contributing to the adverse outcomes of platelet transfusions to neonates.

immunology↗