A transcriptome analysis of basal and stimulated VWF release from endothelial cells derived from patients with type 1 VWD

• Published in: Blood advances 2023-04, Vol.7 (8), p.1477-1487
• Main Authors: Kloosterman, Robert, Zago-Schmitt, Matteo, Grabell, Julie, Thibeault, Lisa, De Lima, Patricia A., Bowman, Mackenzie, Tyryshkin, Kathrin, Hindmarch, Charles C. T., Renwick, Neil, James, Paula
• Format: Article
• Language: English
• Subjects: Endothelial Cells - metabolism; Gene Expression Profiling; Hemorrhage; Humans; MicroRNAs - genetics; RNA, Messenger - genetics; RNA, Messenger - metabolism; Thrombosis and Hemostasis; von Willebrand Disease, Type 1 - genetics; von Willebrand Factor - metabolism
• ISSN: 2473-9529; 2473-9537
• DOI: 10.1182/bloodadvances.2022007884

•Transcriptome-wide differences exist between type 1 VWD and control-derived endothelial cells during basal and stimulated VWF release.•Dysregulation of specific miRNA-mRNA axes may contribute to the pathogenesis of type 1 VWD. [Display omitted] Type 1 von Willebrand disease (VWD) is associated with a reduction in qualitatively normal von Willebrand factor (VWF). Current diagnostic guidelines only take into consideration the contribution of basal VWF levels, despite a lack of correlation with bleeding severity. Defects in stimulated VWF release, which occurs after hemostatic challenge, may contribute to bleeding in type 1 VWD, but the pathogenic mechanisms are poorly defined. In this study, a layered multiomic approach including messenger RNA (mRNA) and microRNA (miRNA) sequencing was used to evaluate transcriptome-wide differences between type 1 VWD- and control-derived endothelial colony forming cells (ECFCs) during basal and stimulated VWF release. ECFCs from 8 patients with type 1 VWD and 4 other patients were included in this study as controls. VWF protein analysis revealed heterogenous responses to stimulation among type 1 VWD and control ECFCs. During basal VWF release, 64 mRNAs and 7 miRNAs were differentially regulated between type 1 VWD and control ECFCs, and 65 putatively pathogenic miRNA-mRNA interactions were identified. During stimulated VWF release, 190 mRNAs and 5 mRNAs were differentially regulated between type 1 VWD and control ECFCs, and 110 putatively pathogenic miRNA-mRNA interactions were identified. Five gene ontology terms including coagulation, regulation of cell shape, and regulation of cell signaling were also differentially regulated in type 1 VWD ECFCs during stimulated release. To our knowledge, we have shown for the first time that transcriptome-wide differences exist between type 1 VWD and control ECFCs. These differences may contribute to bleeding in type 1 VWD, and further investigation may reveal novel biomarkers and therapeutic targets.