title: Platelet factor 4 regulates megakaryopoiesis through low-density lipoprotein receptor-related protein 1 (LRP1) on megakaryocytes.
abstract: Platelet factor 4 (PF4) is a negative regulator of megakaryopoiesis, but its mechanism of action had not been addressed. Low-density lipoprotein (LDL) receptor-related protein-1 (LRP1) has been shown to mediate endothelial cell responses to PF4 and so we tested this receptor's importance in PF4's role in megakaryopoiesis. We found that LRP1 is absent from megakaryocyte-erythrocyte progenitor cells, is maximally present on large, polyploidy megakaryocytes, and near absent on platelets. Blocking LRP1 with either receptor-associated protein (RAP), an antagonist of LDL family member receptors, or specific anti-LRP1 antibodies reversed the inhibition of megakaryocyte colony growth by PF4. In addition, using shRNA to reduce LRP1 expression was able to restore megakaryocyte colony formation in bone marrow isolated from human PF4-overexpressing mice (hPF4(High)). Further, shRNA knockdown of LRP1 expression was able to limit the effects of PF4 on megakaryopoiesis. Finally, infusion of RAP into hPF4(High) mice was able to increase baseline platelet counts without affecting other lineages, suggesting that this mechanism is important in vivo. These studies extend our understanding of PF4's negative paracrine effect in megakaryopoiesis and its potential clinical implications as well as provide insights into the biology of LRP1, which is transiently expressed during megakaryopoiesis.
authors: Department of Pediatrics, Children's Hospital of Philadelphia, PA 19104, USA. lambertm@email.chop.edu
authors: Michele P
authors: MP
authors: Lambert
authors: Yuhuan
authors: Y
authors: Wang
authors: Khalil H
authors: KH
authors: Bdeir
authors: Yvonne
authors: Y
authors: Nguyen
authors: M Anna
authors: MA
authors: Kowalska
authors: Mortimer
authors: M
authors: Poncz
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D026563:LDL-Receptor Related Protein-Associated Protein / Q000235:genetics / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D055015:Megakaryocyte-Erythroid Progenitor Cells / Q000166:cytology / Q000378:metabolism*; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D019899:Paracrine Communication / Q000187:drug effects / Q000502:physiology*; D010978:Platelet Factor 4 / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034061:Thrombopoiesis / Q000187:drug effects / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000906:Antibodies; D026563:LDL-Receptor Related Protein-Associated Protein; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; D010978:Platelet Factor 4