Kouzuki Kagehiro, Umeda Katsutsugu, Hamabata Takayuki, Kamitori Tatsuya, Mikami Takashi, Honda Yoshitaka, Saida Satoshi, Kato Itaru, Baba Shiro, Hiramatsu Hidefumi, Yasumi Takahiro, Niwa Akira, Saito Megumu K, Takita Junko
Department of Pediatrics, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, 606-8507, Japan.
Int J Hematol. 2025 May 28. doi: 10.1007/s12185-025-04004-1.
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.
恩伯格综合征（ES）是一种常染色体显性疾病，其特征为先天性耳聋、原发性淋巴水肿以及易患髓系恶性肿瘤，由GATA2基因突变引起。虽然原发性淋巴水肿是ES的一个重要标志，但由于缺乏合适的实验模型，其病理生理学仍不清楚。在本研究中，我们从两名ES患者中分离出诱导多能干细胞（iPSC）（即ES-iPSC），并通过中胚层祖细胞阶段分析其体外淋巴分化潜能。在添加骨形态发生蛋白4和血管内皮生长因子（VEGF）的无血清、无饲养层的6天培养过程中，由ES-iPSC或野生型iPSC产生的KDR CD34早期中胚层祖细胞具有几乎相同的发育潜能。然而，与OP9基质细胞共培养时，源自ES-iPSC的KDR CD34细胞发育为CD31淋巴管内皮透明质酸受体-1 VEGF受体3淋巴内皮细胞的效率低于源自野生型iPSC的KDR CD34细胞。因此，患者来源的iPSC在淋巴管生成的早期阶段重现了损伤情况，使其成为剖析ES中原发性淋巴水肿病理生理学以及开发潜在治疗方法的有用实验工具。
