Remodeling of fatty acid metabolism in megakaryocytes crucially affects megakaryopoiesis and thrombopoiesis

Ferdinand Kollotzek (Tübingen)1, B. de Jonckheere (Vienna)2, P. Münzer (Tübingen)3, V. Göb (Würzburg)4, M. Fischer (Tübingen)3, K. Mott (Würzburg)4, C. Coman (Wien)5, N. N. Troppmair (Wien)5, M.-C. Manke (Tübingen)3, M. Zdanyte (Tübingen)3, T. Harm (Tübingen)3, M. Sigle (Tübingen)3, D. Kopczynski (Vienna)2, A. Bileck (Vienna)2, C. Gerner (Vienna)2, N. Hoffmann (Vienna)2, A. Assinger (Vienna)2, M. Gawaz (Tübingen)3, D. Stegner (Würzburg)4, H. Schulze (Würzburg)4, R. Ahrends (Vienna)2, O. Borst (Tübingen)3

1Universitätsklinikum Tübingen Innere Medizin III, Kardiologie und Kreislauferkrankungen Tübingen, Deutschland; 2Institute of Analytical Chemistry, University of Vienna Vienna, Österreich; 3Universitätsklinikum Tübingen Innere Medizin III, Kardiologie und Angiologie Tübingen, Deutschland; 4Institute for Experimental Biomedicine, University Hospital Würzburg Würzburg, Deutschland; 5Institute of Analytical Chemistry, University of Vienna Wien, Österreich


Background: Throughout the process of megakaryopoiesis, megakaryocytes (MKs) undergo significant cellular changes, including alterations in their shape and size. These changes are accompanied by the reprogramming of various lipid- and metabolism related signaling pathways, which suggests that the composition and signaling of the phospholipid membrane is also likely to be modified. However, our understanding of how lipids, fatty acid metabolism and dietary change megakaryopoiesis and the signaling pathways involved in these changes remains incomplete.
Aims: Here, we used a lipid-centric multiomics approach to create a quantitative map of the megakaryocyte lipidome during maturation and proplatelet formation. Thus, we want to unravel the molecular mechanisms that drive cell differentiation and function, offering valuable insights into the high potential of fatty acid metabolism and the effect of dietary during MK maturation and proplatelet formation, since there is urgent need to identify new thrombopoietic agents to encounter thrombocytopenic events.
Methods and Results: With the help of the latest quantitative mass spectrum technologies, we assembled a lipid metabolic network of more than 300 proteins involved in lipid transport, synthesis, and degradation that shows substantial regulation during MK maturation. Data reveal that MK differentiation is associated with enhanced expression of lipid-related enzymes and driven by an increased fatty acyl import and de novolipid synthesis. Interfering with fatty acid import and phospholipid synthesis using pharmacological or genetic approaches hindered membrane remodeling, which directly impaired MK polyploidization and proplatelet formation, leading to thrombocytopenia. During megakaryopoiesis, the plasma membrane becomes more negatively charged due to an increase in anionic lipids resulting in recruitment of the proteins CKIP-1 and CK2α to the plasma membrane, which is essential for sufficient platelet production.
Conclusions: This study provides new insights in the complex composition and changes of the phospholipid membrane in megakaryocytes and how fatty acids play a key role in MK maturation and platelet biogenesis suggesting that dietary interventions can influence thrombopoiesis and lipid remodeling.
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