Acupuncture improves transplanted neural stem cells in dementia mice by modulating hippocampal microenvironment via microRNA-124 mediated Notch and Wnt pathways

doi:10.4252/wjsc.v18.i3.114929

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World Journal of Stem Cells

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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. Mar 26, 2026; 18(3): 114929
Published online Mar 26, 2026. doi: 10.4252/wjsc.v18.i3.114929

Acupuncture improves transplanted neural stem cells in dementia mice by modulating hippocampal microenvironment via microRNA-124 mediated Notch and Wnt pathways

Yu-Jiao Li, Xi Chen, Yong-Yin Luo, Jun Chang, Shu-Zhen Liu, Xiao-Qian Shan, Jing-Jing Song, Nan Hao, Xu-He Yan, Wei-Li Gao, Jian-Wei Liu, Lan Zhao

Yu-Jiao Li, Xi Chen, Yong-Yin Luo, Jun Chang, Shu-Zhen Liu, Xiao-Qian Shan, Jing-Jing Song, Nan Hao, Xu-He Yan, Wei-Li Gao, Lan Zhao, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine, Tianjin 300381, China

Jian-Wei Liu, School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China

Co-first authors: Yu-Jiao Li and Xi Chen.

Co-corresponding authors: Jian-Wei Liu and Lan Zhao.

Author contributions: Zhao L contributed to the conceptualization, funding acquisition, project administration, and supervision; Liu JW contributed to the conceptualization, animal modeling and supervision; Li YJ, Chen X, Luo YY, Chang J, Shan XQ, and Song JJ contributed to investigation and methodology; Li YJ and Chen X contributed to writing original draft; Liu SZ, Hao N, Yan XH, and Gao WL contributed to writing-review and editing. All authors have read and agreed to the published version of the manuscript. We designated Zhao L and Liu JW as co-corresponding authors for three key reasons. First, the study’s collaborative nature warrants shared responsibility, ensuring effective post-submission communication and enhancing the paper’s quality. Second, both authors possess complementary expertise, enriching the research with diverse, in-depth perspectives for readers. Third, Zhao L and Liu JW contributed equally throughout the project. There are two main reasons for deciding to designate Li YJ and Chen X as co-first authors. First, this study was conducted as a collaborative effort, and it is reasonable to designate a co- author. Second, both authors contributed equally during the experimental implementation, data processing, plotting and writing of this manuscript. We believe that designating Zhao L and Liu JW as co-corresponding authors and Li YJ and Chen X as co-first authors are suitable for our manuscript as it accurately reflects our team’s spirit of cooperation, equal contribution and diversity.

Supported by National Natural Science Foundation of China, No. 82074533.

Institutional animal care and use committee statement: All procedures involving animals are reviewed and approved by the Tianjin University of Traditional Chinese Medicine, No. TCM-LAEC2022045.

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: The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding authors.

Corresponding author: Lan Zhao, PhD, Professor, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine, No. 88 Changling Road, Xiqing District, Tianjin 300381, China. lanzhao69@163.com

Received: October 11, 2025
Revised: November 5, 2025
Accepted: January 26, 2026
Published online: March 26, 2026
Processing time: 174 Days and 20 Hours

Abstract

BACKGROUND

Neural stem cells (NSCs) transplantation is a promising clinical therapy for Alzheimer’s disease (AD). The Notch and Wnt signaling pathways play important roles in the biological functions of NSCs, and microRNA-124 (miR-124) regulates these pathways through its regulatory effects.

AIM

To explore the mechanism of acupuncture in enhancing the function of transplanted NSCs and their therapeutic potential in AD.

METHODS

This study utilized enzyme-linked immunosorbent assay, western blotting, and real-time fluorescent quantitative polymerase chain reaction, to investigate the effects of acupuncture on the role of miR-124 in regulating the Notch and Wnt signaling pathways, in NSCs transplantation therapy in a mouse model of AD-senescence-accelerated mouse prone 8 mice. An in vitro coculture model of mouse hippocampal brain slices and NSCs was established, and flow cytometry was used to examine the effects of acupuncture on the regulation of cyclin D1, an interactive protein in the Notch and Wnt signaling pathways, and on NSCs proliferation and differentiation.

RESULTS

Acupuncture significantly improved cognitive impairment in AD mice after NSCs transplantation (P < 0.05); inhibited expression of characteristic pathological biomarkers of AD (P < 0.05); and upregulated expression of NSCs-specific neuroproliferation and differentiation biomarkers (P < 0.05). Upregulation of miR-124 modulated the key target genes Notch homolog 1, hairy and enhancer of split 5, and glycogen synthase kinase 3β in the Notch and Wnt signaling pathways (P < 0.05); regulated the Notch and Wnt dual signaling pathways and achieved interaction (P < 0.05); promoted NSCs proliferation and differentiation (P < 0.05); restored damaged cells; and slowed the progression of AD.

CONCLUSION

Acupuncture may improve the hippocampal microenvironment by upregulating miR-124 to regulate the Notch and Wnt dual signaling pathways, promote NSCs proliferation and differentiation, facilitate the repair of damaged neurons, integrate neural circuits, restore biological functions, and improve cognitive impairment in AD mice.

Keywords: Neural stem cells; Hippocampal microenvironment; Acupuncture; MicroRNA-124; Notch signaling pathway; Wnt signaling pathway; Alzheimer’s disease

Core Tip: Acupuncture improved hippocampal microenvironmental dysfunction in a mouse model of Alzheimer’s disease (AD), thereby enhancing the biological activity of transplanted neural stem cells (NSCs). Acupuncture reduced AD-related pathological biomarkers and upregulated microRNA-124, which concurrently targeted Notch homolog 1, hairy and enhancer of split 5, and glycogen synthase kinase 3β, modulating the Notch and Wnt signaling pathways. This dual pathway regulated cyclin D1-mediated NSCs proliferation and differentiation, and promoted neural circuit remodeling. Consequently, AD pathology was markedly suppressed. Our study identified microRNA-124/Notch-Wnt as a promising therapeutic target and suggests that sustained acupuncture is a viable strategy for mitigating irreversible neurofunctional deficits in AD.