Critical shifts in lipid metabolism promote megakaryocyte differentiation and proplatelet formation
- Bianca de Jonckheere1
- Ferdinand Kollotzek2
- Patrick Münzer2
- Vanessa Göb3
- Melina Fischer2
- Kristina Mott3
- Cristina Coman1
- Nina Nicole Troppmair1
- Mailin-Christin Manke2
- Monika Zdanyte2
- Tobias Harm4
- Manuel Sigle4
- Dominik Kopczynski1
- Andrea Bileck1
- Christopher Gerner1
- Nils Hoffmann5
- David Heinzmann4
- Alice Assinger6
- Meinrad Gawaz4
- David Stegner3
- Harald Schulze3
- Oliver Borst2
- Robert Ahrends1
- 1. Institute of Analytical Chemistry, University of Vienna, Austria
- 2. DFG Heisenberg Group Cardiovascular Thromboinflammation and Translational Thrombocardiology, University of Tübingen, Germany
- 3. Institute for Experimental Biomedicine, University Hospital Würzburg, Germany
- 4. Department of Cardiology and Angiology, University of Tübingen, Germany
- 5. Forschungszentrum Jülich GmbH, Institute for Bio- and Geosciences (IBG-5) Jülich, Germany
- 6. Institute of Physiology, Centre of Physiology and Pharmacology, Medical University of Vienna, Austria
Description
During megakaryopoiesis, megakaryocytes (MK) undergo cellular morphological changes with strong modification of membrane composition and lipid signaling. Here we adopt a lipid-centric multiomics approach to create a quantitative map of the MK lipidome during maturation and proplatelet formation. Data reveal that MK differentiation is driven by an increased fatty acyl import and de novo lipid synthesis, resulting in an anionic membrane phenotype. Pharmacological perturbation of fatty acid import and phospholipid synthesis blocked membrane remodeling and directly reduced MK polyploidization and proplatelet formation resulting in thrombocytopenia. The anionic lipid shift during megakaryopoiesis was paralleled by lipid-dependent relocalization of the scaffold protein CKIP-1 and recruitment of the kinase CK2α to the plasma membrane, which seems to be essential for sufficient platelet biogenesis. Overall, this study provides a framework to understand how the MK lipidome is altered during maturation and the impact of MK membrane lipid remodeling on MK kinase signaling involved in thrombopoiesis.