Elevated TNFα induces hyperreactive platelets by reprogramming hematopoietic stem cells in mice

In mouse models, researchers investigated how chronic exposure to the inflammatory cytokine TNFα generates hyperreactive platelets. Using receptor labeling and single-cell RNA sequencing, the team found that megakaryocytes and their progenitors lack TNFα receptors. Instead, chronic TNFα expanded the hematopoietic stem and progenitor cell pool in bone marrow and extramedullary tissues. These expanded cells retained functional repopulation capacity. Activating TNFα receptor 1 signaling proved sufficient to cause platelet hyperreactivity even without progenitor cell expansion. Lineage-tracing experiments showed that chronic TNFα promoted megakaryocyte development through the canonical hematopoietic hierarchy rather than emergency hematopoiesis pathways. The exposure induced a distinct transcriptional program in stem cells and megakaryocytes that persisted through differentiation.