Understanding platelet clearance in health and disease and its feedback to platelet production

• Applicant: Professor Dr. Carsten Deppermann
• Subject Area: Hematology, Oncology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 506633663

Platelets play important roles in thrombosis, hemostasis and inflammation. They are generated by megakaryocytes in the bone marrow. At the end of their lifespan, platelets are cleared by a process that is incompletely understood. Low platelet count (thrombocytopenia) can cause bleeding. Common causes for thrombocytopenia are ITP, sepsis, irradiation, chemotherapy or inflammatory conditions. Using intravital microscopy, I could recently show that aged platelets bound to and were phagocytosed by Kupffer cells. Further, Kupffer cell depletion caused the accumulation of aged platelets in circulation which resulted in impaired hemostatic function. With this proposal, I aim to better understand platelet clearance mechanisms in the liver under basal conditions and disease and how they are linked to platelet production by megakaryocytes in the bone marrow. To achieve this, we will use confocal and intravital microscopy, flow cytometry, immune histochemistry, tissue clearing, primary cell culture and experimental mouse models. Our findings will be verified using human liver slice culture and a humanized mouse. I hypothesize that platelet clearance by Kupffer cells in the liver is a universal process. We will therefore study platelet clearance in different (patho)physiologic settings. Specifically, we will investigate platelet clearance after transfusion of (cold-)stored platelets, of apoptotic platelets, in acute and chronic ITP models, in aged and germfree mice. We will generate and characterize a novel mouse model with a genetic defect in platelet clearance. I also hypothesize that Kupffer cells play an important part in the increased platelet turnover after myocardial infarction. Further, I want to find out if platelet-leukocyte complexes are also cleared by Kupffer cells. Thrombopoietin is a major driver of platelet production in the steady state. IL-6, IL-1 and IGF have been suggested to play a role in situations of acute platelet needs. However, how Kupffer cell-mediated platelet clearance feeds back to platelet production is unknown. I hypothesize that Kupffer cells can stimulate bone marrow megakaryocytes in a direct or indirect fashion with or without the contribution of hepatocytes. Therefore, I will investigate how Kupffer cell-mediated platelet clearance in the steady state and under stress conditions is linked to platelet production in the bone marrow. Finally, to confirm that the mechanisms observed in mice also take place in humans, we will analyze human platelet clearance and a humanized mouse model. With these studies I aim to better understand (patho)physiologic platelet clearance, how it regulates platelet production and how it affects functional outcome, e.g. after myocardial infarction. This will provide us with novel insights into how to prolong platelet lifespan after transfusion, treatment options for thrombocytopenias during ITP or sepsis as well as thromboinflammatory diseases like myocardial infarction.

• DFG Programme: Independent Junior Research Groups