The State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of Education), Division of Nephrology, Nanfang Hospital, Southern Medical University, North Guangshou Avenue 1838, Guangzhou, 510515, Guangdong, People's Republic of China.
Division of Nephrology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, People's Republic of China.
J Hematol Oncol. 2023 Jul 27;16(1):84. doi: 10.1186/s13045-023-01481-x.
Hyperhomocysteinemia (HHcy) is closely associated with thrombotic diseases such as myocardial infarction and stroke. Enhanced platelet activation was observed in animals and humans with HHcy. However, the influence of HHcy on thrombopoiesis remains largely unknown. Here, we reported increased platelet count (PLT) in mice and zebrafish with HHcy. In hypertensive patients (n = 11,189), higher serum level of total Hcy was observed in participants with PLT ≥ 291 × 10/L (full adjusted β, 0.59; 95% CI 0.14, 1.04). We used single-cell RNA sequencing (scRNA-seq) to characterize the impact of Hcy on transcriptome, cellular heterogeneity, and developmental trajectories of megakaryopoiesis from human umbilical cord blood (hUCB) CD34 cells. Together with in vitro and in vivo analysis, we demonstrated that Hcy promoted megakaryocytes (MKs) differentiation via growth hormone (GH)-PI3K-Akt axis. Moreover, the effect of Hcy on thrombopoiesis is independent of thrombopoietin (TPO) because administration of Hcy also led to a significant increase of PLT in homozygous TPO receptor (Mpl) mutant mice and zebrafish. Administration of melatonin effectively reversed Hcy-induced thrombopoiesis in mice. ScRNA-seq showed that melatonin abolished Hcy-facilitated MK differentiation and maturation, inhibited the activation of GH-PI3K-Akt signaling. Our work reveals a previously unrecognized role of HHcy in thrombopoiesis and provides new insight into the mechanisms by which HHcy confers an increased thrombotic risk.Trial Registration clinicaltrials.gov Identifier: NCT00794885.
高同型半胱氨酸血症（HHcy）与心肌梗死和中风等血栓性疾病密切相关。在 HHcy 的动物和人类中观察到增强的血小板活化。然而，HHcy 对血小板生成的影响在很大程度上仍然未知。在这里，我们报道了 HHcy 小鼠和斑马鱼中血小板计数（PLT）增加。在高血压患者（n=11189）中，PLT≥291×10/L 的参与者血清总同型半胱氨酸水平较高（全调整β，0.59；95%CI 0.14，1.04）。我们使用单细胞 RNA 测序（scRNA-seq）来描述 Hcy 对人类脐带血（hUCB）CD34 细胞中巨核细胞生成的转录组、细胞异质性和发育轨迹的影响。结合体外和体内分析，我们证明 Hcy 通过生长激素（GH）-PI3K-Akt 轴促进巨核细胞（MK）分化。此外，Hcy 对血小板生成的影响独立于血小板生成素（TPO），因为 Hcy 的给药也导致纯合 TPO 受体（Mpl）突变小鼠和斑马鱼的 PLT 显著增加。褪黑素的给药有效地逆转了小鼠中 Hcy 诱导的血小板生成。scRNA-seq 显示褪黑素消除了 Hcy 促进的 MK 分化和成熟，抑制了 GH-PI3K-Akt 信号的激活。我们的工作揭示了 HHcy 在血小板生成中的一个以前未被认识的作用，并为 HHcy 增加血栓形成风险的机制提供了新的见解。试验注册临床Trials.gov 标识符：NCT00794885。
