Identification of MMP1 as a novel risk factor for intracranial aneurysms in ADPKD using iPSC models.
Identification of MMP1 as a novel risk factor for intracranial aneurysms in ADPKD using iPSC models.
复制标题
DOI：
10.1038/srep30013
复制
发表时间：
2016-07-15
影响因子：
4.6
通讯作者：
Osafune K
中科院分区：
文献类型：
--
作者：
Ameku T;Taura D;Sone M;Numata T;Nakamura M;Shiota F;Toyoda T;Matsui S;Araoka T;Yasuno T;Mae S;Kobayashi H;Kondo N;Kitaoka F;Amano N;Arai S;Ichisaka T;Matsuura N;Inoue S;Yamamoto T;Takahashi K;Asaka I;Yamada Y;Ubara Y;Muso E;Fukatsu A;Watanabe A;Sato Y;Nakahata T;Mori Y;Koizumi A;Nakao K;Yamanaka S;Osafune K
心血管并发症是常染色体显性多囊肾病（ADPKD）的主要死亡原因，颅内动脉瘤（ICA）引起的蛛网膜下腔出血是最严重的并发症之一。ICAs在ADPKD中的诊断和治疗策略尚未完全确定。我们从7名ADPKD患者中获得了诱导多能干细胞（iPSCs），其中包括4名具有ICAs的患者。与来自非adpkd受试者的iPSCs相比，从ADPKD-iPSCs分化的血管细胞显示Ca2+进入和基因表达谱的改变。我们发现一种金属酶基因基质金属蛋白酶（MMP） 1的表达水平在ipsc来源的ADPKD患者的内皮中特异性升高。此外，我们在354例ADPKD患者中证实了血清MMP1水平与ICAs发展之间的相关性，表明高血清MMP1水平可能是一个新的危险因素。这些结果表明，具有adpkd特异性iPSCs的细胞疾病模型可用于研究疾病机制并识别新的疾病相关分子或危险因素。
Cardiovascular complications are the leading cause of death in autosomal dominant polycystic kidney disease (ADPKD), and intracranial aneurysm (ICA) causing subarachnoid hemorrhage is among the most serious complications. The diagnostic and therapeutic strategies for ICAs in ADPKD have not been fully established. We here generated induced pluripotent stem cells (iPSCs) from seven ADPKD patients, including four with ICAs. The vascular cells differentiated from ADPKD-iPSCs showed altered Ca2+ entry and gene expression profiles compared with those of iPSCs from non-ADPKD subjects. We found that the expression level of a metalloenzyme gene, matrix metalloproteinase (MMP) 1, was specifically elevated in iPSC-derived endothelia from ADPKD patients with ICAs. Furthermore, we confirmed the correlation between the serum MMP1 levels and the development of ICAs in 354 ADPKD patients, indicating that high serum MMP1 levels may be a novel risk factor. These results suggest that cellular disease models with ADPKD-specific iPSCs can be used to study the disease mechanisms and to identify novel disease-related molecules or risk factors.