Dynamic regulation of neural stem cell state transitions by NOTCH1-REST transcriptional axis

doi:10.4252/wjsc.117617

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World Journal of Stem Cells

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1948-0210

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.

World J Stem Cells. Aug 26, 2026; 18(8): 117617
Published online Aug 26, 2026. doi: 10.4252/wjsc.117617

Dynamic regulation of neural stem cell state transitions by NOTCH1-REST transcriptional axis

Zhi-Chong Xie, Xiao-Yong Zhao, Rui-Hua Xiong, Xiao-Li Zhang, Wei Yang

Zhi-Chong Xie, Xiao-Yong Zhao, Department of Neurosurgery, The Fifth Hospital of Guangzhou Medical University, Guangzhou 510700, Guangdong Province, China

Rui-Hua Xiong, Department of Oncology, Shenzhen Hospital of Guangzhou University of Chinese Medicine (Futian), Guangzhou 518034, Guangdong Province, China

Xiao-Li Zhang, Department of Obstetrics and Gynecology, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou 510632, Guangdong Province, China

Wei Yang, Department of Physical Examination, Guangzhou Xinhai Hospital, Guangzhou 510275, Guangdong Province, China

Co-first authors: Zhi-Chong Xie and Xiao-Yong Zhao.

Co-corresponding authors: Xiao-Li Zhang and Wei Yang.

Author contributions: Xie ZC and Zhao XY contributed equally to this work and should be regarded as co-first authors. Xie ZC designed the study, performed organoid experiments, and drafted the manuscript; Xiong RH conducted data analysis, including single-cell pseudotime and multi-omics integration; Zhao XY supervised the project, contributed to study design, and revised the manuscript critically for important intellectual content; Zhang XL participated in experimental design, coordinated sample collection, and contributed to data interpretation; Yang W performed metabolomics analysis and assisted with imaging experiments. All authors reviewed and approved the final version of the manuscript. Zhang XL and Yang W jointly served as co-corresponding authors because they contributed to study supervision, experimental coordination, data interpretation, and critical manuscript revision, and they share responsibility for correspondence and the integrity of the work.

AI contribution statement: No AI-assisted technologies were used in the preparation of this manuscript.

Supported by Guangzhou Municipal Science and Technology Bureau University Project, No. 2025A03J3232; Guangdong Provincial Graduate Education Innovation Project, No. 2024JGXM_158; and Futian District Health and Wellness Project of Shenzhen, No. FTWS059.

Institutional animal care and use committee statement: All animal experiments were approved by the Animal Ethics Committee of the Fifth Hospital of Guangzhou Medical University (No. P2025-25012).

Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.

ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.

Data sharing statement: All data generated or analyzed during this study are included in this article and/or its Supplementary material files. Further enquiries can be directed to the corresponding author.

Corresponding author: Wei Yang, Department of Physical Examination, Guangzhou Xinhai Hospital, No. 167 Xingang West Road, Haizhu District, Guangzhou 510275, Guangdong Province, China. yuki20152025@163.com

Received: January 4, 2026
Revised: March 31, 2026
Accepted: June 15, 2026
Published online: August 26, 2026
Processing time: 252 Days and 1.6 Hours

Abstract

BACKGROUND

The regulatory role of the neurogenic locus notch homolog protein 1 (NOTCH1)-RE1-silencing transcription factor (REST) transcriptional axis in neural stem cell (NSC) dormancy-activation transitions remains poorly understood.

AIM

To clarify the temporal, epigenetic, and metabolic mechanisms by which the NOTCH1–REST axis regulates NSC/neural progenitor cell (NPC) state transitions and neural repair.

METHODS

Public human embryonic prefrontal cortex single-cell RNA sequencing data, human-induced pluripotent stem cell-derived human NSCs, human neural organoids, multimodal omics, and a mouse spinal cord injury model were integrated. Pseudotime analysis was used to infer NSC/NPC state trajectories, and functional perturbation, organoid intervention, exploratory assay for transposase-accessible chromatin using sequencing/chromatin immunoprecipitation sequencing, metabolomics, live imaging, and in vivo assays were performed for validation.

RESULTS

REST was enriched in quiescent-like NSC/NPC states and declined during activation, whereas NOTCH1 increased during the intermediate activation phase, indicating a sequential rather than simultaneous regulatory relationship. REST inhibition promoted G1/S progression, EdU incorporation, and activation dynamics, while NOTCH1 activation partially counterbalanced these effects. Stage-resolved organoid single-cell RNA sequencing identified SOX2-, NES/Nestin-, and PAX6-expressing NSC/NPC-like populations, supporting the relevance of the organoid model. Exploratory assay for transposase-accessible chromatin using sequencing and chromatin immunoprecipitation sequencing profiles suggested stage-associated changes in chromatin accessibility and transcription factor binding, and metabolomics indicated that REST inhibition was associated with enhanced central carbon metabolism and glycolysis-related remodeling. In the spinal cord injury model, REST inhibition promoted NSC marker re-expression in the lesion area and improved motor recovery.

CONCLUSION

These findings support the NOTCH1-REST axis as a time-dependent regulatory switch governing NSC/NPC state transitions through coordinated transcriptional, epigenetic, and metabolic remodeling, and suggest REST-targeted modulation as a potential strategy for neural repair.

Keywords: Neural stem cells; Neurogenic locus notch homolog protein 1-RE1-silencing transcription factor axis; Epigenetic; Organoid model; Neural repair

Core Tip: This study unveils the neurogenic locus notch homolog protein 1-RE1-silencing transcription factor axis as a pivotal molecular switch controlling neural stem cell dormancy-activation transitions. By integrating transcriptional, epigenetic, and metabolic analyses, it elucidates the dynamic regulatory interplay of neurogenic locus notch homolog protein 1 and RE1-silencing transcription factor, offering crucial insights into neural stem cell state transitions. The findings present promising targets for central nervous system injury repair and regenerative therapies for neurodegenerative diseases.