Efficient megakaryopoiesis and platelet production require phospholipid remodeling and PUFA uptake through CD36

Abstract

Lipids contribute to hematopoiesis and membrane properties and dynamics, however, little is known about the role of lipids in megakaryopoiesis. Here, a lipidomic analysis of megakaryocyte progenitors, megakaryocytes, and platelets revealed a unique lipidome progressively enriched in polyunsaturated fatty acid (PUFA)-containing phospholipids. In vitro, inhibition of both exogenous fatty acid functionalization and uptake and de novo lipogenesis impaired megakaryocyte differentiation and proplatelet production. In vivo, mice on a high saturated fatty acid diet had significantly lower platelet counts, which was prevented by eating a PUFA-enriched diet. Fatty acid uptake was largely dependent on CD36, and its deletion in mice resulted in thrombocytopenia. Moreover, patients with a CD36 loss-of-function mutation exhibited thrombocytopenia and increased bleeding. Our results suggest that fatty acid uptake and regulation is essential for megakaryocyte maturation and platelet production, and that changes in dietary fatty acids may be a novel and viable target to modulate platelet counts.

Metabolomics profile and machine learning prediction of treatment responses in immune thrombocytopenia: A prospective cohort study

“…37 Barrachina et al's study underscored the significant role played by dietary polyunsaturated fatty acids and CD36 fatty acid transporters in megakaryocyte differentiation, maturation and platelet production. 38 Kong et al found that impaired bone marrow endothelial progenitor cells, characterized by reduced migration, angiogenesis, elevated reactive oxygen species levels and apoptosis, play a role in the pathogenesis of corticosteroid-resistant ITP. 4 Furthermore, atorvastatin, which regulates lipid metabolism, significantly improved the number and function of bone marrow endothelial progenitor cells in patients with corticosteroids-resistant ITP.…”

“…Barrachina et al. 's study underscored the significant role played by dietary polyunsaturated fatty acids and CD36 fatty acid transporters in megakaryocyte differentiation, maturation and platelet production 38 . Kong et al.…”

What It Takes To Be a Platelet: Evolving Concepts in Platelet Production

“…[26][27][28][29] A body of experimental data has demonstrated that a large amount of surface membrane necessary for proplatelet elaboration is provided by the membrane reservoir present in the megakaryocyte cytoplasm. 21,22,30,31 A variety of transgenic mice lacking F-actin-regulating proteins such as Cofilin1, Cdc42 (cell division cycle 42), and tropomodulin-3 30,32,33 or exhibiting defective lipid homeostasis such as in CD36-deficient or SR-BI (scavenger receptor class B member 1)-deficient mice 34,35 present with an aberrant DMS and concomitant defective proplatelet production and thrombocytopenia. A recent study 36 reported unaltered proplatelet production despite defective DMS formation in megakaryocytes in transgenic mice carrying a mutation within GPIbα (glycoprotein Ib-alpha) that renders it unable to bind to flnA (filamin A).…”

Ferroptosis-Regulated Cell Death as a Therapeutic Strategy for Neurodegenerative Diseases: Current Status and Future Prospects

“…It has been acknowledged that severe peroxidation of membranes containing polyunsaturated fatty acids (PUFAs) is the primary driving force behind ferroptosis, which not only is regulated by lipid and iron metabolism but also involves amino acid metabolism and signaling transduction. 8 The critical steps involved in ferroptosis include intracellular free iron accumulation, glutathione depletion, and peroxidation of PUFA-rich membranes. 9 These steps are summarized in Figure 1.…”