Abstract Number: PB0953
Meeting: ISTH 2021 Congress
Background: Platelets are affected by many factors, such as infectious or aseptic inflammation. Tumor necrosis factor α (TNFα) is an important inflammatory cytokine. However, the role of TNFα in thrombopoiesis remains largely elusive.
Aims: This study aims to investigate the effect of TNFα on megakaryopoiesis (MK) and platelet production.
Results: Here, we report an increase of TNFα in patients with essential thrombocythemia, which is characterized by megakaryocyte burden. Meanwhile, a significant higher TNFα level is also observed in patients with normal platelet reconstitution after HSCT compared with those with prolonged thrombocytopenia. The ex vivo study demonstrates that escalating concentrations of TNFα differentially modulate human CD34+ cells development toward MK and platelet production. Specifically, a low concentration of TNFα 0.5 ng/ml tends to promote MK maturation, stress fiber formation, proplatelet formation and platelet production. Otherwise, a high concentration of TNFα 10 ng/ml or more exhibits a remarkably inhibitory effect on these processes. Of note, the distinct effect of TNFα on MK is mainly dependent on TNFR1 rather than TNFR2. The Transcriptome analysis of cultured MK treated with TNFα shows significant reprogramming of cell adhesion and migration related genes. Further investigations indicate that TNFα 0.5 ng/ml and 10 ng/ml also differentially regulate cell cytoskeleton molecules in MK, including RhoA/ROCK1/Cofilin/MLC2, which have been reported to regulate cell cytoskeleton rearrangement. In addition, both MAPK-ERK1/2 and PI3K-Akt signaling pathways are differentially activated by different concentrations of TNFα. In mice, low (0.5μg) or high doses (5μg) of TNFα administration also differentially affect short-term platelet recovery after bone marrow transplantation. Bone marrow MK number and location with vascular sinusoids in TNFα treated group are also significantly different with control group.
Conclusions: Our data shows a distinct effect of TNFα on regulating MK maturation and thrombopoiesis, and may provide new insights into its treatment implications in platelet abnormality diseases.
To cite this abstract in AMA style:Chu T, Hu S, Qi J, Han Y, Wu D. Bifunctional Effect of Inflammatory Cytokine TNFα on Human Megakaryopoiesis and Platelet Production [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/bifunctional-effect-of-inflammatory-cytokine-tnf%ce%b1-on-human-megakaryopoiesis-and-platelet-production/. Accessed December 7, 2021.
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