Dendritic spine formation and synapse maturation in transcription factor-induced human iPSC-derived neurons

Waka Lin; Shusaku Shiomoto; Saki Yamada; Hikaru Watanabe; Yudai Kawashima; Yuichi Eguchi; Koichi Muramatsu; Yuko Sekino

doi:10.1016/j.isci.2023.106285

Dendritic spine formation and synapse maturation in transcription factor-induced human iPSC-derived neurons

iScience. 2023 Feb 27;26(4):106285. doi: 10.1016/j.isci.2023.106285. eCollection 2023 Apr 21.

Authors

Waka Lin¹, Shusaku Shiomoto¹, Saki Yamada¹, Hikaru Watanabe¹, Yudai Kawashima¹, Yuichi Eguchi¹, Koichi Muramatsu¹, Yuko Sekino^{2

3}

Affiliations

¹ Biomedical R&D Department, Biomedical Business Center, Ricoh Company, Ltd., Kawasaki, Kanagawa 210-0821, Japan.
² Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
³ Institute for Drug Discovery Innovation, Bunkyo-ku, Tokyo 113-0033, Japan.

Abstract

Synaptic maturation is reportedly limited in human induced pluripotent stem cell (iPSC)-derived neurons. Notably, their ability to reach postnatal-like stages and form dendritic spines has been difficult to demonstrate unless using long-term cultured organoids. Recent transcription factor (TF)-based induction methods allow the accelerated generation of differentiated neurons, which offers an unprecedented opportunity to address further progression into late developmental stages. Herein, we report on a comprehensive time-course study of TF-induced iPSC neurons cultured in vitro through an intrinsic maturation program following neurogenesis. Moreover, we determined the transcriptional and morphological sequences of key developmental events associated with spinogenesis, including the conversion of drebrin to its brain-specific isoform A and the N-methyl-D-aspartate (NMDA) receptor subunit switch. TF-induced iPSC neurons successfully acquired structural and functional synaptic maturity, which will critically expand their utility in modeling higher brain functions and disorders.

Keywords: Cell biology; Neuroscience; Stem cells research.