von Willebrand disease-specific defects and proteomic signatures in endothelial colony–forming cells
Year: 2025
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Endothelial cells are crucial for hemostasis as they produce von Willebrand factor (VWF). von Willebrand disease (VWD) results from a deficiency of, or defects in, VWF. OBJECTIVES: We analyzed the endothelial compartment of VWD patients with an unexplained decrease in VWF level or nonresponse to 1-8-deamino-D-arginine vasopressin (DDAVP) using endothelial colony-forming cells (ECFCs). METHODS: Thirteen healthy controls and 10 VWD type 1 and 2 patients were included, and a total of 29 ECFC clones were obtained. Plasma was analyzed, and ECFCs were morphologically and functionally characterized by quantitative polymerase chain reaction, ELISA, imaging, migration assay, and mass spectrometry. RESULTS: VWF plasma levels were reduced in all patients. ECFCs were categorized into 2 previously defined transcriptional clusters and matched between patients and controls. Four ECFC clones, all from DDAVP nonresponders, retained VWF in the endoplasmic reticulum. Cluster 1 ECFCs from DDAVP nonresponders closed more slowly in the migration assay and had lower basal release of VWF antigen than control ECFCs. Proteomic data of ECFC lysates showed overlap in clustering with RNA profiles, including ALDHA1, TGFB1, and other endothelial-to-mesenchymal/inflammatory markers. However, no patient group-specific phenotype was observed. Finally, regulated secretion of VWF and Weibel-Palade body count in ECFCs correlated with various secretory machinery components. CONCLUSION: Lower plasma VWF was linked to reduced production and secretion by ECFCs obtained from patients. Furthermore, nonresponse to DDAVP in some patients was explained by VWF retention in the endoplasmic reticulum. The correlation between functional aspects of ECFCs and their quantitative polymerase chain reaction and proteome profiles yielded potential targets for further research.
Authors: Sebastiaan N.J. Laan, Stijn Groten, Richard J. Dirven, Petra E. Bürgisser, Frank W.G. Leebeek, Iris van Moort, Maartje van den Biggelaar, Ruben Bierings, Jeroen Eikenboom, Noord Holland, Martijn Brands, Sjoerd Koopman, Laura Bukkems, Michael Cloesmeijer, Alexander Janssen, Karin Fijnvandraat, Samantha Gouw, Ron Mathôt, Lotte Haverman, Emile van den Akker, Maartje van den Biggelaar, Masja de Haas, Sander Meijer, Jan Voorberg, Jessica Del Castillo Alferez, Huan Zhang, Johan Boender, Stephan Meijer, Karina Meijer, Sean de Jong, Geertje Goedhart, Anske van der Bom, Mettine Bos, Jeroen Eikenboom, Felix van der Meer, Sebastiaan Laan, Saskia Schols, Zuid Holland, Ruben Bierings, Lex Burdorf, Marjon Cnossen, Jan Hazelzet, Elise Huisman, Marieke Kruip, Frank Leebeek, Nikki van Leeuwen, Hester Lingsma, Moniek de Maat, Iris van Moort, Suzanne Polinder, Simone Reitsma, Eliza Roest, Ryanne Arisz, Lorenzo Romano, Wala Al Arashi, Shannon van Hoorn, Tine Goedhart, Caroline Mussert, Diaz Prameyllawati, Carin Uyl, Nathalie Jansen, Kathelijn Fischer, Hans Kristian Ploos van Amstel, Rolf Urbanus, Minka Zivkovic, Annelien Bredenoord, Rieke van der Graaf, Lieke Baas, Roger Schutgens, Mariëtte Driessens
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,750
Funders: CSL Behring, Takeda Pharmaceutical Company, Landsteiner Foundation for Blood Transfusion Research, Amsterdam University Medical Centers, Universiteit Leiden, Radboud Universiteit, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Leids Universitair Medisch Centrum, Universitair Medisch Centrum Groningen, Radboud Universitair Medisch Centrum, Nederlandse Vereniging voor Trombose en Hemostase, Swedish Orphan Biovitrum, Stichting Haemophilia, Erasmus Universitair Medisch Centrum Rotterdam
OpenAlex ID: W4410114053