Carbohydrate-Mediated Platelet Clearance

点击翻译按钮获取中文摘要

Project Summary The human body produces and removes 1011 platelets daily to maintain a normal steady-state platelet count. Production can be greatly increased under conditions of platelet destruction. We provided the first evidence that survival of platelets is intimately tied to surface glycans, and have shown that platelets with impaired Siaα2-3Galβ1-4GlcNAc structures are removed in the liver by Kupffer cells and hepatocytes. Our data also showed that binding of desialylated platelets, i.e. platelets bearing terminal Galβ1-4GlcNAc (LacNAc) structures, to the hepatocyte-specific Ashwell-Morell Receptor (AMR) increases thrombopoietin (TPO) production via JAK2-STAT3 signaling in hepatocytes. Thus the data suggest that desialylated platelet function as direct communicators between the bone marrow (BM) and hepatocytes. Here, we continue to investigate the platelet-hepatocyte-BM communication mechanism and the hypothesis that systemic signals altered in the absence of AMR regulate BM homeostasis will be solidified. We will identify novel systemic factors and decipher the mechanisms by which these factors regulate the BM hematopoietic niche. Our current data implicates a novel role of platelets as a regulator of BM vascular and mesenchymal cells, thereby affecting hematopoiesis via hepatocyte-secreted factor NRG4, the specific ErbB4 ligand. Recent genome wide association studies (GWAS) give credence to our preliminary data: Single-nucleotide polymorphisms (SNPs) in NRG4 and NRG3 genes have been associated with changes in peripheral red blood cell (RBC) and platelet count. We propose to investigate BM vascular, perivascular and mesenchymal progenitor cell populations and HSC function in the absence of AMR-mediated platelet clearance. Platelet surface glycans will be measured in platelets and plasma from individuals with SNP in NRG3/4 (Aim 1); and determine the molecular mechanisms by which NRG4 and ErbB4 regulate the HSC niche in the absence of hepatic AMR-mediated platelet clearance (Aim 2).