Purpose Arterio-venous malformation (AVM) is a high-flow vascular malformation consisting of a tangle of poorly formed vessels with low resistance (nidus) in place of a functional capillary network. Management of AVM remains challenging. Understanding of the pathogenesis of AVM may lead to improved treatment. The role of somatic mutations in embryonic stem cells (ESCs) and in other vascular anomalies have led us to investigate the presence of an ESC-like population in extracranial AVM.
Methods Extracranial AVM tissue samples from 11 patients were stained for induced pluripotent stem cell (iPSC) markers OCT4, SOX2, NANOG, KLF4 and c-MYC using immunohistochemical staining. In-situ hybridization was performed on six AVM tissue samples to determine transcript expression of the iPSC markers. Western blotting and RT-qPCR were performed on two AVM-derived primary cell lines to determine protein and transcript expression of these iPSC markers, respectively. Immunofluorescence staining was performed on two of the AVM tissue samples to investigate co-localization of these iPSC markers.
Results Immunohistochemical staining demonstrated expression of OCT4, SOX2, KLF4 and c-MYC but not NANOG on the endothelium and media of the lesional vessels and cells within the stroma of the nidus in all 11 AVM samples. In-situ hybridization and RT-qPCR confirmed transcript expression of all five iPSC markers. Western blotting showed protein expression of all iPSC markers except NANOG. Immunofluorescence staining demonstrated an OCT4+/SOX2+/KLF4+/c-MYC+ ESC-like population within the endothelium and media of the lesional vessels and cells within the stroma of the AVM nidus.
Conclusions This study demonstrated an ESC-like population within the AVM nidus. Understanding the precise role of this primitive population in AVM may lead to improved treatment of this challenging condition.