PUBLICATION
Hyperhomocysteinemia potentiates megakaryocyte differentiation and thrombopoiesis via GH-PI3K-Akt axis
- Authors
- Lei, W., Liu, Z., Su, Z., Meng, P., Zhou, C., Chen, X., Hu, Z., Xiao, A., Zhou, M., Huang, L., Zhang, Y., Qin, X., Wang, J., Zhu, F., Nie, J.
- ID
- ZDB-PUB-230728-48
- Date
- 2023
- Source
- Journal of Hematology & Oncology 16: 8484 (Other)
- Registered Authors
- Keywords
- Growth hormone, Hyperhomocysteinemia, Megakaryocyte, ScRNA-seq, Thrombopoiesis
- MeSH Terms
-
- Animals
- Blood Platelets
- Cell Differentiation
- Growth Hormone/pharmacology
- Humans
- Hyperhomocysteinemia*/complications
- Megakaryocytes
- Melatonin*/pharmacology
- Mice
- Phosphatidylinositol 3-Kinases
- Proto-Oncogene Proteins c-akt/genetics
- Thrombopoiesis/genetics
- Zebrafish
- PubMed
- 37501059 Full text @ J. Hematol. Oncol.
Citation
Lei, W., Liu, Z., Su, Z., Meng, P., Zhou, C., Chen, X., Hu, Z., Xiao, A., Zhou, M., Huang, L., Zhang, Y., Qin, X., Wang, J., Zhu, F., Nie, J. (2023) Hyperhomocysteinemia potentiates megakaryocyte differentiation and thrombopoiesis via GH-PI3K-Akt axis. Journal of Hematology & Oncology. 16:8484.
Abstract
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 × 109/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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping