Critical shifts in lipid metabolism promote megakaryocyte differentiation and proplatelet formation

Bianca de Jonckheere, Ferdinand Kollotzek, Patrick Münzer, Vanessa Göb, Melina Fischer, Kristina Mott, Cristina Coman, Nina Nicole Troppmair, Mailin Christin Manke, Monika Zdanyte, Tobias Harm, Manuel Sigle, Dominik Kopczynski, Andrea Bileck, Christopher Gerner, Nils Hoffmann, David Heinzmann, Alice Assinger, Meinrad Gawaz, David StegnerHarald Schulze, Oliver Borst (Corresponding author), Robert Ahrends (Corresponding author)

Publications: Contribution to journalArticlePeer Reviewed

Abstract

During megakaryopoiesis, megakaryocytes (MKs) 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 effect of MK membrane lipid remodeling on MK kinase signaling involved in thrombopoiesis.

Original languageEnglish
Pages (from-to)835-852
Number of pages18
JournalNature Cardiovascular Research
Volume2
Issue number9
DOIs
Publication statusPublished - Sept 2023

Austrian Fields of Science 2012

  • 301302 Lipidomics research
  • 301114 Cell biology
  • 301303 Medical biochemistry
  • 302032 Cardiology

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