TNFα drives platelet hyperreactivity and thromboinflammation through regulation of hematopoietic stem and progenitor cells.
- 1Washington University School of Medicine
Abstract
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.
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BibTeX
@misc{siner2026tnfα,
title = {{TNFα drives platelet hyperreactivity and thromboinflammation through regulation of hematopoietic stem and progenitor cells.}},
author = {J. I. Siner and M. Brakhane and K. Platten and A. Ajanel and E. T. Tun and L. Antunes Heck and T. Girard and N. Lasky and M. Fulbright and C. Letson and Y.-A. Kang and C. N. Morrell and S. T. Oh and J. Di Paola},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.28.755049},
url = {https://www.biorxiv.org/content/10.64898/2026.09.28.755049v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - TNFα drives platelet hyperreactivity and thromboinflammation through regulation of hematopoietic stem and progenitor cells.
AU - J. I. Siner
AU - M. Brakhane
AU - K. Platten
AU - A. Ajanel
AU - E. T. Tun
AU - L. Antunes Heck
AU - T. Girard
AU - N. Lasky
AU - M. Fulbright
AU - C. Letson
AU - Y.-A. Kang
AU - C. N. Morrell
AU - S. T. Oh
AU - J. Di Paola
PY - 2026
DA - 2026/09/28
PB - bioRxiv
DO - 10.64898/2026.09.28.755049
UR - https://www.biorxiv.org/content/10.64898/2026.09.28.755049v1
AB - 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.
ER -