Department of Hematology, Fukushima Medical University, Fukushima, Japan.
Blood Adv. 2019 Jul 23;3(14):2128-2143. doi: 10.1182/bloodadvances.2019000222.
Endothelial dysfunction in the early phases of hematopoietic stem cell transplantation (HSCT) contributes to a common pathology between transplant-associated thrombotic microangiopathy (TA-TMA) and graft-versus-host disease (GVHD), which are serious complications of HSCT. Growth arrest-specific (Gas) 6 structurally belongs to the family of plasma vitamin K-dependent proteins working as a cofactor for activated protein C, and has growth factor-like properties through its interaction with receptor tyrosine kinases of the TAM family: Tyro3, Axl, and Mer. Serum Gas6 levels were significantly increased in HSCT patients with grade II to IV acute GVHD (aGVHD), and Gas6 and Mer expression levels were upregulated in aGVHD lesions of the large intestine and skin. The increased serum Gas6 levels were also correlated with elevated lactate dehydrogenase, d-dimer, and plasmin inhibitor complex values in HSCT patients with aGVHD. In human umbilical vein endothelial cells (ECs), exogenous Gas6 or the exposure of sera isolated from patients with grade III aGVHD to ECs induced the downregulation of thrombomodulin and the upregulation of PAI-1, as well as the upregulation of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, which were inhibited by UNC2250, a selective Mer tyrosine kinase inhibitor. In mouse HSCT models, we observed hepatic GVHD with hepatocellular apoptosis, necrosis, and fibrosis, as well as TA-TMA, which is characterized pathologically by thrombosis formation in the microvasculature of the liver and kidney. Of note, intravenous administration of UNC2250 markedly suppressed GVHD and TA-TMA in these mouse HSCT models. Our findings suggest that the Gas6-Mer axis is a promising target for TA-TMA after GVHD.
造血干细胞移植（HSCT）早期的内皮功能障碍导致移植相关血栓性微血管病（TA-TMA）和移植物抗宿主病（GVHD）之间存在共同的病理机制，这两种并发症都是 HSCT 的严重并发症。生长停滞特异性蛋白 6（Gas）6 在结构上属于血浆维生素 K 依赖性蛋白家族，作为活化蛋白 C 的辅因子发挥作用，并通过与其家族的受体酪氨酸激酶（TAM）家族成员：Tyro3、Axl 和 Mer 相互作用具有生长因子样特性。HSCT 患者发生 II 级至 IV 级急性移植物抗宿主病（aGVHD）时，血清 Gas6 水平显著升高，并且 Gas6 和 Mer 在 aGVHD 大肠和皮肤病变中的表达水平上调。在发生 aGVHD 的 HSCT 患者中，血清 Gas6 水平升高与乳酸脱氢酶、D-二聚体和纤溶酶抑制剂复合物值升高相关。在人脐静脉内皮细胞（EC）中，外源性 Gas6 或来自 III 级 aGVHD 患者的血清暴露于 EC 可诱导血栓调节蛋白下调和 PAI-1 上调，以及细胞间黏附分子-1 和血管细胞黏附分子-1 上调，这些作用可被 UNC2250 抑制，UNC2250 是一种选择性 Mer 酪氨酸激酶抑制剂。在小鼠 HSCT 模型中，我们观察到肝 GVHD 伴有肝细胞凋亡、坏死和纤维化，以及 TA-TMA，其病理学特征是肝脏和肾脏微血管中的血栓形成。值得注意的是，静脉内给予 UNC2250 可显著抑制这些小鼠 HSCT 模型中的 GVHD 和 TA-TMA。我们的研究结果表明，Gas6-Mer 轴是 GVHD 后 TA-TMA 的一个有前途的靶点。
