Neuroprotective Potential of L-Glutamate Transporters in Human Induced Pluripotent Stem Cell-Derived Neural Cells against Excitotoxicity

Takahashi, Kanako; Ishibashi, Yuto; Chujo, Kaori; Suzuki, Ikuro; Sato, Kaoru

doi:10.3390/ijms241612605

Open AccessArticle

Neuroprotective Potential of L-Glutamate Transporters in Human Induced Pluripotent Stem Cell-Derived Neural Cells against Excitotoxicity

by

Kanako Takahashi

¹,

Yuto Ishibashi

²,

Kaori Chujo

¹,

Ikuro Suzuki

² and

Kaoru Sato

^1,*

¹

Laboratory of Neuropharmacology, Division of Pharmacology, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki-city, Kanagawa 210-9501, Japan

²

Department of Electronics, Graduate School of Engineering, Tohoku Institute of Technology, Miyagi 982-8577, Japan

^*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2023, 24(16), 12605; https://doi.org/10.3390/ijms241612605

Submission received: 18 May 2023 / Revised: 1 August 2023 / Accepted: 5 August 2023 / Published: 9 August 2023

(This article belongs to the Special Issue Pluripotent Stem Cells and Organoids on Disease Modeling and Therapeutic Potentials)

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Abstract

Human induced pluripotent stem cell (hiPSC)-derived neural cells have started to be used in safety/toxicity tests at the preclinical stage of drug development. As previously reported, hiPSC-derived neurons exhibit greater tolerance to excitotoxicity than those of primary cultures of rodent neurons; however, the underlying mechanisms remain unknown. We here investigated the functions of L-glutamate (L-Glu) transporters, the most important machinery to maintain low extracellular L-Glu concentrations, in hiPSC-derived neural cells. We also clarified the contribution of respective L-Glu transporter subtypes. At 63 days in vitro (DIV), we detected neuronal circuit functions in hiPSC-derived neural cells by a microelectrode array system (MEA). At 63 DIV, exposure to 100 μM L-Glu for 24 h did not affect the viability of neural cells. 100 µM L-Glu in the medium decreased to almost 0 μM in 60 min. Pharmacological inhibition of excitatory amino acid transporter 1 (EAAT1) and EAAT2 suppressed almost 100% of L-Glu decrease. In the presence of this inhibitor, 100 μM L-Glu dramatically decreased cell viability. These results suggest that in hiPSC-derived neural cells, EAAT1 and EAAT2 are the predominant L-Glu transporters, and their uptake potentials are the reasons for the tolerance of hiPSC-derived neurons to excitotoxicity.

Keywords: excitotoxicity; human induced pluripotent stem cell; neuron; astrocyte; L-glutamate transporter; EAAT1; EAAT2

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MDPI and ACS Style

Takahashi, K.; Ishibashi, Y.; Chujo, K.; Suzuki, I.; Sato, K. Neuroprotective Potential of L-Glutamate Transporters in Human Induced Pluripotent Stem Cell-Derived Neural Cells against Excitotoxicity. Int. J. Mol. Sci. 2023, 24, 12605. https://doi.org/10.3390/ijms241612605

AMA Style

Takahashi K, Ishibashi Y, Chujo K, Suzuki I, Sato K. Neuroprotective Potential of L-Glutamate Transporters in Human Induced Pluripotent Stem Cell-Derived Neural Cells against Excitotoxicity. International Journal of Molecular Sciences. 2023; 24(16):12605. https://doi.org/10.3390/ijms241612605

Chicago/Turabian Style

Takahashi, Kanako, Yuto Ishibashi, Kaori Chujo, Ikuro Suzuki, and Kaoru Sato. 2023. "Neuroprotective Potential of L-Glutamate Transporters in Human Induced Pluripotent Stem Cell-Derived Neural Cells against Excitotoxicity" International Journal of Molecular Sciences 24, no. 16: 12605. https://doi.org/10.3390/ijms241612605

APA Style

Takahashi, K., Ishibashi, Y., Chujo, K., Suzuki, I., & Sato, K. (2023). Neuroprotective Potential of L-Glutamate Transporters in Human Induced Pluripotent Stem Cell-Derived Neural Cells against Excitotoxicity. International Journal of Molecular Sciences, 24(16), 12605. https://doi.org/10.3390/ijms241612605

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Neuroprotective Potential of L-Glutamate Transporters in Human Induced Pluripotent Stem Cell-Derived Neural Cells against Excitotoxicity

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