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Updated: Apr 16, 2026
A Patient-Derived Xenograft Model for Venous Malformation
Published on: June 15, 2020
Identification of pathological CD133+ endothelial cells in venous malformations
Carrie J Shawber1,2, Averill Clapp2, Noa Shapiro-Franklin2
1Division of Reproductive Sciences, Department of Ob/Gyn, Columbia University Irving Medical Center Vagelos College of Physicians & Surgeons, and New York Presbyterian/Morgan Stanley Children's Hospital, New York, NY, United States.
Insights
Researchers identified a novel CD133+ venous malformation endothelial cell (VMEC) in patients. These cells exhibit progenitor markers and genetic variants, contributing to venous malformation development and recapitulating the phenotype in mouse models.
Area of Science:
- Vascular Biology
- Developmental Biology
- Genetics
Background:
- Venous malformations (VMs) are congenital vascular anomalies characterized by dilated vascular channels.
- Previous research indicated pathogenic variants in endothelial cells (ECs) of VMs.
- Recent findings identified the EC progenitor marker CD133 on VM endothelium.
Purpose of the Study:
- To investigate the role of CD133+ endothelial cells (ECs) in the pathobiology of venous malformations (VMs).
- To characterize the phenotype and genetic makeup of CD133+ VMECs.
- To assess the capacity of CD133+ VMECs to recapitulate VM phenotypes in vivo.
Main Methods:
- Isolation of VM cells using CD133 as a marker.
- Characterization of isolated cells via RT-PCR, FACS, and immunofluorescence.
- Whole exome sequencing (WES) for genetic variant analysis.
- Assessment of AKT/ERK activation and cell proliferation.
- Xenografting of CD133+ cells in mice to evaluate VM phenotype recapitulation.
Main Results:
- CD133+ VM endothelial cells (VMECs) were isolated, expressing both progenitor and mature EC markers.
- WES identified pathogenic variants in genes like PIK3CA and TEK within CD133+ VMECs.
- These cells demonstrated increased proliferation and AKT activation.
- Xenografted CD133+ VMECs with identified variants successfully recapitulated clinical VM phenotypes.
Conclusions:
- A novel cell type, CD133+ VMECs, was identified in venous malformations.
- These cells exhibit progenitor characteristics and harbor genetic variants associated with VMs.
- CD133+ VMECs contribute to VM pathobiology and can recapitulate the disease phenotype in vivo.
Introduction:
Venous malformations (VMs) are congenital malformations of the venous system. Histologically, they are composed of dilated vascular channels. Prior studies have demonstrated that CD31 + endothelial cells (ECs) in VMs have pathogenic variants. Recent studies by our group found that the EC progenitor marker, CD133+, was expressed on VM endothelium in patient tissues. We hypothesized that a CD133+ VM endothelial cells contributes to VM pathobiology.
Methods:
VM cells were isolated from resected venous malformation tissues or fluid using CD133 as a marker. Isolated VM populations were characterized by quantative RT-PCR, fluorescence-activated cell sorting (FACS) and immunofluorescence staining (IF) for the expression of progenitor and mature EC genes/proteins. Cells underwent whole exome sequencing (WES) to probe for genetic variants. AKT and ERK activation status was assessed by Western blot and IF, and cell proliferation determined. Isolated CD133+ cells were xenografted in mice and their ability to recapitulate VM phenotype was assessed by histological analysis, IF and colormetric staining.
Results:
CD133+ cells isolated from VMs expressed progenitor and mature EC genes and proteins, and we termed them CD133+ VM endothelial cells (CD133+ VMECs). WES revealed CD133+ VMECs had pathogenic variants and variants of uncertain significance in genes reported in VMs, PIK3CA and TEK. CD133+ VMECs had increase proliferation and a subset had increase nuclear phospho-AKT. When implanted into a xenograft model, CD133+ VMECs with PIK3CA and TEK variants recapitulated clinical VM phenotypes.
Conclusion:
We have identified a novel cell type in VMs, CD133+ VMECs that express EC progenitor proteins, demonstrating incomplete or misdirected differentiation down the EC lineage and are capable of recapitulate the phenotype in a mouse model.
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