Critical shifts in lipid metabolism promote megakaryocyte differentiation and proplatelet formation (Shotgun lipidomics assays after inhibition with FSG67 and Triacsin C)

During megakaryopoiesis, megakaryocytes (MK) undergo cellular morphological changes with strong modification of membrane composition and lipid signaling. Here we adopt a lipid-centric multi-omics 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.

Shotgun lipidomics assays after inhibition with FSG67 and Triacsin C are reported in the current assay MTBLS6083
Shotgun lipidomics assays without inhibition are reported in MTBLS6082
Targeted lipidomics assay without inhibition are reported in MTBLS6084

在巨核细胞生成（megakaryopoiesis）过程中，巨核细胞（简称MK）会发生细胞形态学改变，同时伴随膜组分与脂质信号通路的显著重塑。本研究采用以脂质为核心的多组学策略，构建了MK成熟及前血小板形成过程中脂质组（lipidome）的定量图谱。研究数据显示，MK分化受脂肪酸酰基摄取增强与从头脂质合成增加所驱动，最终形成阴离子膜表型。对脂肪酸摄取与磷脂合成进行药理学干预，可阻断膜重塑过程，并直接抑制MK多倍体化与前血小板形成，最终引发血小板减少症。巨核细胞生成过程中的阴离子脂质位移，伴随支架蛋白CKIP-1的脂质依赖性重定位，以及激酶CK2α向质膜的募集，这一过程似乎对充足的血小板生成至关重要。总体而言，本研究为理解MK脂质组在成熟过程中的改变，以及MK膜脂质重塑对参与血小板生成的MK激酶信号通路的影响提供了理论框架。

经FSG67与Triacsin C干预后的鸟枪法脂质组学分析数据，已收录于数据集MTBLS6083；未进行干预的鸟枪法脂质组学分析数据收录于MTBLS6082；未进行干预的靶向脂质组学分析数据收录于MTBLS6084。