Gene Expression Profiles of Human Cerebral Organoids Identify PPAR Pathway and PKM2 as Key Markers for Oxygen-Glucose Deprivation and Reoxygenation

Naoki Iwasa; Takeshi K Matsui; Naohiko Iguchi; Kaoru Kinugawa; Naritaka Morikawa; Yoshihiko M Sakaguchi; Tomo Shiota; Shinko Kobashigawa; Mari Nakanishi; Masaya Matsubayashi; Riko Nagata; Sotaro Kikuchi; Tatsuhide Tanaka; Nobuyuki Eura; Takao Kiriyama; Tesseki Izumi; Kozue Saito; Hiroshi Kataoka; Yuichi Saito; Wataru Kimura; Akio Wanaka; Yuhei Nishimura; Eiichiro Mori; Kazuma Sugie

doi:10.3389/fncel.2021.605030

Gene Expression Profiles of Human Cerebral Organoids Identify PPAR Pathway and PKM2 as Key Markers for Oxygen-Glucose Deprivation and Reoxygenation

Front Cell Neurosci. 2021 Jun 8:15:605030. doi: 10.3389/fncel.2021.605030. eCollection 2021.

Authors

Naoki Iwasa¹, Takeshi K Matsui^{1

2}, Naohiko Iguchi¹, Kaoru Kinugawa¹, Naritaka Morikawa², Yoshihiko M Sakaguchi², Tomo Shiota¹, Shinko Kobashigawa², Mari Nakanishi², Masaya Matsubayashi², Riko Nagata², Sotaro Kikuchi², Tatsuhide Tanaka³, Nobuyuki Eura¹, Takao Kiriyama¹, Tesseki Izumi¹, Kozue Saito¹, Hiroshi Kataoka¹, Yuichi Saito⁴, Wataru Kimura⁴, Akio Wanaka³, Yuhei Nishimura⁵, Eiichiro Mori^{2

6}, Kazuma Sugie¹

Affiliations

¹ Department of Neurology, Nara Medical University, Kashihara, Japan.
² Department of Future Basic Medicine, Nara Medical University, Kashihara, Japan.
³ Department of Anatomy and Neuroscience, Nara Medical University, Kashihara, Japan.
⁴ Laboratory for Heart Regeneration, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan.
⁵ Department of Integrative Pharmacology, Mie University Graduate School of Medicine, Tsu, Japan.
⁶ V-iCliniX Laboratory, Nara Medical University, Kashihara, Japan.

Abstract

Ischemic stroke is one of the most common neurological diseases. However, the impact of ischemic stroke on human cerebral tissue remains largely unknown due to a lack of ischemic human brain samples. In this study, we applied cerebral organoids derived from human induced pluripotent stem cells to evaluate the effect of oxygen-glucose deprivation/reoxygenation (OGD/R). Pathway analysis showed the relationships between vitamin digestion and absorption, fat digestion and absorption, peroxisome proliferator-activated receptor (PPAR) signaling pathway, and complement and coagulation cascades. Combinational verification with transcriptome and gene expression analysis of different cell types revealed fatty acids-related PPAR signaling pathway and pyruvate kinase isoform M2 (PKM2) as key markers of neuronal cells in response to OGD/R. These findings suggest that, although there remain some limitations to be improved, our ischemic stroke model using human cerebral organoids would be a potentially useful tool when combined with other conventional two-dimensional (2D) mono-culture systems.

Keywords: cerebral organoid; ferritin light chain; human induced pluripotent stem cells; ischemic stroke; oxygen-glucose deprivation/reoxygenation; peroxisome proliferator-activated receptor; pyruvate kinase M2.

Copyright © 2021 Iwasa, Matsui, Iguchi, Kinugawa, Morikawa, Sakaguchi, Shiota, Kobashigawa, Nakanishi, Matsubayashi, Nagata, Kikuchi, Tanaka, Eura, Kiriyama, Izumi, Saito, Kataoka, Saito, Kimura, Wanaka, Nishimura, Mori and Sugie.