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281 Notch1 Regulates Hepatic Thrombopoietin Production

Program: Oral and Poster Abstracts
Type: Oral
Session: 301. Vasculature, Endothelium, Thrombosis and Platelets: Basic and Translational: The Multimodal Platelet; Discovery of Novel Platelet Functions and Applications From Cancers to Thrombocytopenias
Hematology Disease Topics & Pathways:
Research, Fundamental Science
Saturday, December 9, 2023: 5:00 PM

Yueyue Sun1,2*, Huan Tong1,2*, Lingyu Zeng1,2*, Kailin Xu1,2* and Jianlin Qiao, PhD1,3

1Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
2Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
3Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou City, Jiangsu Province, China

Notch signaling is highly conserved and regulates cell-fate decisions in several developmental processes and cell functions. However, a role for Notch in hepatic thrombopoietin (TPO) production has not been described. We noted that mice with a deficiency in hepatic Notch1 had thrombocytopenia, and so investigated TPO production and other features of platelets in these mice. We found that the liver ultrastructure and hepatocyte function were comparable between control mice and Notch1-deficient mice. However, the Notch1-deficient mice had significantly lower plasma TPO and hepatic TPO mRNA levels, concomitant with lower numbers of circulating platelets and impaired megakaryocyte differentiation and maturation. Addition of exogenous TPO rescued megakaryocyte maturation and circulating platelet numbers. Additionally, JAK2/STAT3 phosphorylation was significantly inhibited in Notch1-deficient hepatocytes. RNA-seq analysis showed significantly reduced JAK-STAT signaling. JAK2/STAT3 phosphorylation and TPO production was also impaired in purified cultured Notch1-deficient hepatocytes after treatment with desialylated platelets. Interestingly, Notch1 deficiency downregulated the expression of HES5 but not HES1. Moreover, desialylated platelets promoted the binding of HES5 to JAK2/STAT3, leading to JAK2/STAT3 phosphorylation and pathway activation. Furthermore, blockage of Dll4 on desialylated platelets inhibited hepatocyte Notch1 activation and HES5 expression, JAK2/STAT3 phosphorylation and subsequent TPO production. In conclusion, our study identifies a novel regulatory role of Notch1 in hepatic TPO production, indicating that it might be a target for modulating TPO level.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH