A pluripotent stem cell model of Emberger syndrome reveals reduced lymphatic endothelial differentiation

Emberger syndrome (ES), an autosomal dominant disorder characterized by congenital deafness, primary lymphedema, and predisposition to myeloid malignancies, is caused by mutations in the GATA2 gene. Although primary lymphedema is an important hallmark of ES, the pathophysiology remains unclear due to the lack of a suitable experimental model. In this study, we isolated induced pluripotent stem cells (iPSCs) from two patients with ES (i.e., ES-iPSCs) and analyzed their in vitro lymphatic differentiation potential via the mesodermal progenitor stage. KDR⁺ CD34⁺ early mesodermal progenitors generated from either ES-iPSCs or wild-type iPSCs during a 6-days serum- and feeder-free culture supplemented with bone morphogenetic protein 4 and vascular endothelial growth factor (VEGF) had almost equivalent developmental potential. However, upon co-culture with OP9 stromal cells, KDR⁺ CD34⁺ cells derived from ES-iPSCs developed into CD31⁺ lymphatic vessel endothelial hyaluronan receptor-1⁺ VEGF receptor 3⁺ lymphatic endothelial cells less efficiently than KDR⁺ CD34⁺ cells derived from wild-type iPSCs. Thus, patient-derived iPSCs recapitulate impairments at an early stage of lymphangiogenesis, making them a useful experimental tool for dissecting the pathophysiology of primary lymphedema in ES and developing potential therapeutic approaches.