Identification of MMP1 as a novel risk factor for intracranial aneurysms in ADPKD using iPSC models

• DOI: 10.1038/srep30013
• Publication Date: 2016-07-15T09:49:08Z
• Authors: Tomonaga Ameku; Daisuke Taura; Masakatsu Sone; Tomohiro Numata; Masahiro Nakamura; Fumihiko Shiota; Taro Toyoda; Satoshi Matsui; Toshikazu Araoka; Tetsuhiko Yasuno; Shin-Ichi Mae; Hatasu Kobayashi; Naoya Kondo; Fumiyo Kitaoka; Naoki Amano; Sayaka Arai; Tomoko Ichisaka; Norio Matsuura; Sumiko Inoue; Takuya Yamamoto; Kazutoshi Takahashi; Isao Asaka; Yasuhiro Yamada; Yoshifumi Ubara; Eri Muso; Atsushi Fukatsu; Akira Watanabe; Yasunori Sato; Tatsutoshi Nakahata; Yasuo Mori; Akio Koizumi; Kazuwa Nakao; Shinya Yamanaka; Kenji Osafune
• Keywords: Male; 0301 basic medicine; TRPP Cation Channels; Induced Pluripotent Stem Cells; Cell Differentiation; Intracranial Aneurysm; Mice, SCID; DNA Methylation; Middle Aged; Subarachnoid Hemorrhage; Polycystic Kidney, Autosomal Dominant; Article; 3. Good health; Mice; 03 medical and health sciences; Mice, Inbred NOD; Risk Factors; Animals; Humans; Female; Matrix Metalloproteinase 1; Biomarkers; Cells, Cultured; Aged

AbstractCardiovascular 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.