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

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

doi:10.1038/srep30013

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

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 YamamotoKazutoshi 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

Research output: Contribution to journal › Article › peer-review

28 Citations (Scopus)

Abstract

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 Ca 2+ 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.

Original language	English
Article number	30013
Journal	Scientific reports
Volume	6
DOIs	https://doi.org/10.1038/srep30013
Publication status	Published - 2016 Jul 15
Externally published	Yes

ASJC Scopus subject areas

General

Access to Document

10.1038/srep30013

Cite this

Ameku, T., Taura, D., Sone, M., Numata, T., Nakamura, M., Shiota, F., Toyoda, T., Matsui, S., Araoka, T., Yasuno, T., Mae, S. I., Kobayashi, H., Kondo, N., Kitaoka, F., Amano, N., Arai, S., Ichisaka, T., Matsuura, N., Inoue, S., ... Osafune, K. (2016). Identification of MMP1 as a novel risk factor for intracranial aneurysms in ADPKD using iPSC models. Scientific reports, 6, [30013]. https://doi.org/10.1038/srep30013

Ameku, T, Taura, D, Sone, M, Numata, T, Nakamura, M, Shiota, F, Toyoda, T, Matsui, S, Araoka, T, Yasuno, T, Mae, SI, 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 2016, 'Identification of MMP1 as a novel risk factor for intracranial aneurysms in ADPKD using iPSC models', Scientific reports, vol. 6, 30013. https://doi.org/10.1038/srep30013

@article{68d1902e9cca41128af2c51c8d6ed413,

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

abstract = "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 Ca 2+ 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.",

author = "Tomonaga Ameku and Daisuke Taura and Masakatsu Sone and Tomohiro Numata and Masahiro Nakamura and Fumihiko Shiota and Taro Toyoda and Satoshi Matsui and Toshikazu Araoka and Tetsuhiko Yasuno and Mae, {Shin Ichi} and Hatasu Kobayashi and Naoya Kondo and Fumiyo Kitaoka and Naoki Amano and Sayaka Arai and Tomoko Ichisaka and Norio Matsuura and Sumiko Inoue and Takuya Yamamoto and Kazutoshi Takahashi and Isao Asaka and Yasuhiro Yamada and Yoshifumi Ubara and Eri Muso and Atsushi Fukatsu and Akira Watanabe and Yasunori Sato and Tatsutoshi Nakahata and Yasuo Mori and Akio Koizumi and Kazuwa Nakao and Shinya Yamanaka and Kenji Osafune",

note = "Funding Information: The authors would like to thank Drs Knut Woltjen, Ken Tsuchiya, Toshio Mochizuki, Sizuko Fujita, Masanori Kugita, Tatsuya Suwabe, Junichi Hoshino, Satoru Muto, Kazushige Hanaoka, Shigeo Horie and Eiji Higashihara for their valuable scientific discussions, Peter Karagiannis for reading the manuscript, and Yurina Takaishi for her valuable administrative support. This work was partially supported by Otsuka Pharmaceutical Co., Ltd., by a Grant-in-Aid for Progressive Renal Diseases Research from the Ministry of Health, Labour and Welfare of Japan, by the Japan Society for the Promotion of Science (JSPS) through its {"}Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program){"}, by research grants from the Leading Project of MEXT, by the Japan Science and Technology Agency (JST) through Precursory Research for Embryonic Science and Technology (PRESTO) and the JST Yamanaka iPS cell special project, and by iPS Cell Research Fund.",

year = "2016",

month = jul,

day = "15",

doi = "10.1038/srep30013",

language = "English",

volume = "6",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Identification of MMP1 as a novel risk factor for intracranial aneurysms in ADPKD using iPSC models

AU - Ameku, Tomonaga

AU - Taura, Daisuke

AU - Sone, Masakatsu

AU - Numata, Tomohiro

AU - Nakamura, Masahiro

AU - Shiota, Fumihiko

AU - Toyoda, Taro

AU - Matsui, Satoshi

AU - Araoka, Toshikazu

AU - Yasuno, Tetsuhiko

AU - Mae, Shin Ichi

AU - Kobayashi, Hatasu

AU - Kondo, Naoya

AU - Kitaoka, Fumiyo

AU - Amano, Naoki

AU - Arai, Sayaka

AU - Ichisaka, Tomoko

AU - Matsuura, Norio

AU - Inoue, Sumiko

AU - Yamamoto, Takuya

AU - Takahashi, Kazutoshi

AU - Asaka, Isao

AU - Yamada, Yasuhiro

AU - Ubara, Yoshifumi

AU - Muso, Eri

AU - Fukatsu, Atsushi

AU - Watanabe, Akira

AU - Sato, Yasunori

AU - Nakahata, Tatsutoshi

AU - Mori, Yasuo

AU - Koizumi, Akio

AU - Nakao, Kazuwa

AU - Yamanaka, Shinya

AU - Osafune, Kenji

N1 - Funding Information: The authors would like to thank Drs Knut Woltjen, Ken Tsuchiya, Toshio Mochizuki, Sizuko Fujita, Masanori Kugita, Tatsuya Suwabe, Junichi Hoshino, Satoru Muto, Kazushige Hanaoka, Shigeo Horie and Eiji Higashihara for their valuable scientific discussions, Peter Karagiannis for reading the manuscript, and Yurina Takaishi for her valuable administrative support. This work was partially supported by Otsuka Pharmaceutical Co., Ltd., by a Grant-in-Aid for Progressive Renal Diseases Research from the Ministry of Health, Labour and Welfare of Japan, by the Japan Society for the Promotion of Science (JSPS) through its "Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program)", by research grants from the Leading Project of MEXT, by the Japan Science and Technology Agency (JST) through Precursory Research for Embryonic Science and Technology (PRESTO) and the JST Yamanaka iPS cell special project, and by iPS Cell Research Fund.

PY - 2016/7/15

Y1 - 2016/7/15

N2 - 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 Ca 2+ 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.

AB - 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 Ca 2+ 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.

UR - http://www.scopus.com/inward/record.url?scp=84978633433&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84978633433&partnerID=8YFLogxK

U2 - 10.1038/srep30013

DO - 10.1038/srep30013

M3 - Article

C2 - 27418197

AN - SCOPUS:84978633433

SN - 2045-2322

VL - 6

JO - Scientific Reports

JF - Scientific Reports

M1 - 30013

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this