Background: Lipids represent an extremely vast class of biomolecules, with essential roles in energy homeostasis, membrane structure, and signaling. Recent studies have uncovered that, lipids are key drivers of cell fate decisions during hematopoiesis. However, the contribution of lipids to megakaryopoiesis is unknown.

Aims: Define the trajectory and role of key lipids essential for megakaryocyte differentiation and platelet production.

Methods: We used targeted mass spectrometry to obtain a lipidomic profile of murine bone marrow hematopoietic stem and progenitor cells (HSPC), primary megakaryocyte progenitors, mature megakaryocytes, and platelets. Then, we targeted the incorporation and biosynthesis of fatty acids in vitro. Finally, we administered a high-fat-diet to mice to investigate how changes in dietary fatty acids affect megakaryocyte differentiation and platelet formation.

Results: Analysis of HSPC lipidomes revealed that cell populations clustered into distinct populations, with enrichment in polyunsaturated fatty acids (PUFAs) distinguishing mature from immature megakaryocytes. In primary murine HSPCs, inhibition of acyl-coA synthetase, an enzyme essential for fatty acid metabolism, profoundly decreased megakaryocyte differentiation up to 70%. Similarly, MK maturation was significantly attenuated up to 80% after inhibition of de novo lipogenesis. To examine fatty acid incorporation, we supplemented HSPCs with saturated (palmitic, 16:0) and unsaturated (linoleic, 18:2) fatty acids, which significantly increased megakaryocyte area. Extending this in vivo, mice fed a high-fat-diet with increased palmitic acid and reduced PUFAs had significantly larger megakaryocytes, but reduced platelet counts compared with mice fed a standard chow diet.

Conclusion(s): Our data reveal that fatty acid metabolism and synthesis are critical for megakaryocyte differentiation. Increasing dietary saturated fatty acids and reducing PUFAs significantly altered both megakaryocyte maturation and platelet production, suggesting that thrombopoiesis can be modified in vivo by diet alone. Further explorations will clarify whether lipid uptake and biosynthesis pathways can be targeted therapeutically to modulate platelet levels.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/thrombopoiesis-has-a-unique-lipidomic-profile-enriched-in-polyunsaturated-fatty-acids-that-facilitates-megakaryocyte-maturation-and-platelet-production/