TY - JOUR
T1 - Modelling urea-cycle disorder citrullinemia type 1 with disease-specific iPSCs
AU - Yoshitoshi-Uebayashi, Elena Yukie
AU - Toyoda, Taro
AU - Yasuda, Katsutaro
AU - Kotaka, Maki
AU - Nomoto, Keiko
AU - Okita, Keisuke
AU - Yasuchika, Kentaro
AU - Okamoto, Shinya
AU - Takubo, Noriyuki
AU - Nishikubo, Toshiya
AU - Soga, Tomoyoshi
AU - Uemoto, Shinji
AU - Osafune, Kenji
N1 - Funding Information:
The authors are grateful to Shin-Ichi Mae, Tomomi Sudo, Toshiko Sato, Kanae Mitsunaga, Takuya Yamamoto, Peter Karagiannis, Hokahiro Katayama, Takayuki Kawai, Satoshi Ogiso, Sadahiko Kita, Ken Fukumitsu, Takamichi Ishii (Kyoto University), Kaori Igarashi, Saya Sato, Hiroko Maki, Mayu Homma, Maki Ohishi (Keio University) and Michelle Ong (University of the Phillipines) for technical supports and helpful suggestions. This research was supported by the Japan Agency for Medical Research and Development through its research grant “Core Center for iPS Cell Research, Research Center Network for Realization of Regenerative Medicine” and “Research Project for Practical Applications of Regenerative Medicine”.
Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2017/5/6
Y1 - 2017/5/6
N2 - Citrullinemia type 1 (CTLN1) is a urea cycle disorder (UCD) caused by mutations of the ASS1 gene, which is responsible for production of the enzyme argininosuccinate synthetase (ASS), and classically presented as life-threatening hyperammonemia in newborns. Therapeutic options are limited, and neurological sequelae may persist. To understand the pathophysiology and find novel treatments, induced pluripotent stem cells (iPSCs) were generated from a CTLN1 patient and differentiated into hepatocyte-like cells (HLCs). CTLN1-HLCs have lower ureagenesis, recapitulating part of the patient's phenotype. L-arginine, an amino acid clinically used for UCD treatment, improved this phenotype in vitro. Metabolome analysis revealed an increase in tricarboxylic acid (TCA) cycle metabolites in CTLN1, suggesting a connection between CTLN1 and the TCA cycle. This CTLN1-iPSC model improves the understanding of CTLN1 pathophysiology and can be used to pursue new therapeutic approaches.
AB - Citrullinemia type 1 (CTLN1) is a urea cycle disorder (UCD) caused by mutations of the ASS1 gene, which is responsible for production of the enzyme argininosuccinate synthetase (ASS), and classically presented as life-threatening hyperammonemia in newborns. Therapeutic options are limited, and neurological sequelae may persist. To understand the pathophysiology and find novel treatments, induced pluripotent stem cells (iPSCs) were generated from a CTLN1 patient and differentiated into hepatocyte-like cells (HLCs). CTLN1-HLCs have lower ureagenesis, recapitulating part of the patient's phenotype. L-arginine, an amino acid clinically used for UCD treatment, improved this phenotype in vitro. Metabolome analysis revealed an increase in tricarboxylic acid (TCA) cycle metabolites in CTLN1, suggesting a connection between CTLN1 and the TCA cycle. This CTLN1-iPSC model improves the understanding of CTLN1 pathophysiology and can be used to pursue new therapeutic approaches.
KW - Argininosuccinate synthetase
KW - Citrullinemia type 1
KW - Hepatocyte
KW - L-arginine
KW - Urea cycle disorder
KW - iPSC
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U2 - 10.1016/j.bbrc.2017.03.037
DO - 10.1016/j.bbrc.2017.03.037
M3 - Article
C2 - 28302489
AN - SCOPUS:85015395819
SN - 0006-291X
VL - 486
SP - 613
EP - 619
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 3
ER -