Decoding Blood Platelet Production: The Intricate Role of Lipids

Introduction During megakaryopoiesis and consecutive platelet production, megakaryocytes undergo cellular morphological changes which are associated with the reprogramming of signaling pathways. Moreover, membrane composition and lipid signaling are expected to be strongly modified. However, the knowledge of how lipids are modulated and which pathways are involved is still lacking.

Method Here, we adopt a lipid-centric multiomics approach applying the SIMPLEX protocol [1], which allows for simultaneous lipid and protein sample preparation, to create a quantitative map of the murine megakaryocyte lipidome during maturation and proplatelet formation. Mass spectrometry-based findings were combined with both in vitro and in vivo methodologies to functionally analyse and elucidate the underlying mechanisms of megakaryocyte maturation and proplatelet formation.

Fig. 1 Lipid-driven functional regulation and underlying mechanisms of MK maturation and thrombopoiesis; The study focuses on the functional analysis and regulation of MK maturation, using a multiomics approach and incorporating both in vitro and in vivo methodologies. Isolated hematopoietic stem cells from murine bone marrow were subjected to a 7-day differentiation protocol with TPO. The SIMPLEX workflow was used to comprehensively determine the general molecular composition of MKs. The results revealed significant anionic lipid membrane remodeling and relocalization of the CKIP-1/CK2α complex to the plasma membrane, which appear to be essential for adequate platelet biogenesis.

Results Our data reveal that megakaryocyte differentiation is associated with enhanced expression of lipid-related enzymes and driven by an increased fatty acyl import and de novo lipid synthesis, resulting in the modulation towards an anionic membrane phenotype. Pharmacological perturbation of fatty acid import and phospholipid synthesis proved to block membrane remodeling and directly reduced megakaryocyte polyploidization and proplatelet formation, leading to thrombocytopenia.

Furthermore, the anionic lipid shift during megakaryopoiesis is accompanied by the relocalization of the scaffold protein CKIP-1 and recruitment of the kinase CK2α to the plasma membrane, which is essential for platelet biogenesis ([Fig. 1]).

Conclusion Overall, this study provides a framework to understand how the megakaryocyte lipidome is altered during maturation and proplatelet formation and the effect of membrane lipid remodeling on megakaryocyte kinase signaling involved in thrombopoiesis.

Publication History

Article published online:
26 February 2024

• References

• 1 Coman C.. et al. Simultaneous Metabolite, Protein, Lipid Extraction (SIMPLEX): A Combinatorial Multimolecular Omics Approach for Systems Biology. Mol Cell Proteomics 2016; 15 (04) p 1453-66