Exercise combined with induced pluripotent stem cells enhances the Wnt1-Lmx1a loop in the midbrain of Parkinsonian mice to alleviate Parkinsonian symptoms

doi:10.4252/wjsc.v17.i9.109330

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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

Basic Study

World J Stem Cells. Sep 26, 2025; 17(9): 109330
Published online Sep 26, 2025. doi: 10.4252/wjsc.v17.i9.109330

Exercise combined with induced pluripotent stem cells enhances the Wnt1-Lmx1a loop in the midbrain of Parkinsonian mice to alleviate Parkinsonian symptoms

Xing Jiang, Zhi-Min Lu, Qing-Lu Wang, Ying Luo, Jie Zhang

Xing Jiang, Zhi-Min Lu, Jie Zhang, College of Medical Laboratory, Qilu Medical University, Zibo 250300, Shandong Province, China

Xing Jiang, Zhi-Min Lu, Qing-Lu Wang, College of Sport and Health, Shandong Sport University, Jinan 250102, Shandong Province, China

Ying Luo, Department of Clinical Laboratory, Zibo Central Hospital, Zibo 255000, Shandong Province, China

Co-first authors: Xing Jiang and Zhi-Min Lu.

Co-corresponding authors: Ying Luo and Jie Zhang.

Author contributions: Jiang X and Lu ZM contributed equally to this manuscript and are co-first authors. Jiang X, Lu ZM, and Luo Y conceived and designed research, performed experiment, and drafted manuscript; Jiang X and Lu ZM analyzed data, interpreted results of experiments, and prepared figures; Wang QL and Zhang J edited and revised manuscript. Luo Y and Zhang J contributed equally as co-corresponding author. All the authors have read and agreed to the published version of the manuscript and have agreed to be personally accountable for the author’s contributions and answer any questions related to the accuracy or integrity of any part of the work.

Supported by the Central Government Guides Local Science and Technology Development Funds, No. YDZX2022091; and General Program of Natural Sciences of Qilu Medical University, No. X24ZKQN03.

Institutional animal care and use committee statement: All animal experiments were approved by the Animal Experiment Ethics Committee of Shandong Sport University, No. 2023KY00012.

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: Details of the animal model construction are provided in the methods section and supporting information.

Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

Corresponding author: Jie Zhang, PhD, College of Medical Laboratory, Qilu Medical University, No. 2018 Jiangmenglu Road, Zibo 250300, Shandong Province, China. zhangjie@qlmu.edu.cn

Received: May 9, 2025
Revised: June 18, 2025
Accepted: August 20, 2025
Published online: September 26, 2025
Processing time: 139 Days and 1.4 Hours

Abstract

BACKGROUND

The therapeutic potential of induced pluripotent stem cells (iPSCs) for Parkinson’s disease (PD) has been demonstrated. Exercise can also modulate metabolism to improve motor dysfunction in PD patients.

AIM

To investigate the therapeutic effect of exercise combined with iPSCs in a PD mouse model and explore the underlying mechanisms.

METHODS

In this study, we included 10 normal mice and 40 PD model mice, which were divided into five groups: The control group (n = 10), the sedentary PD group (St group, n = 10), the exercise PD group (E group, n = 10), the iPSC-treated PD group (T group, n = 10), and the combined exercise and iPSC-treated PD group (ET group, n = 10). The T and ET groups received cell injection therapy, while the E and ET groups underwent an 8-week exercise intervention. After the intervention, behavioral tests were performed on mice from all groups. Serum levels of epinephrine (EPI) and nerve growth factor were measured, and the expression of Wnt1, Lmx1a, and other factors related to the Wnt signaling pathway in the midbrain of mice were assessed.

RESULTS

The motor ability of the T group was higher than that of the St group, but the difference was not significant. However, the protein and gene expression levels of Wnt1, Lmx1a, Neurog2, and TH in the T group were significantly higher than those in the St group (P < 0.01). Compared with the T group, the motor ability of the E group was significantly enhanced (P < 0.01), and the gene expression level of Wnt1 in the midbrain of the E group was significantly higher than that of the T group (P < 0.05). The levels of EPI and nerve growth factor were increased in both the E and ET groups. Exercise can improve motor dysfunction in PD, increase EPI levels, and elevate Wnt1 levels. However, western blot results revealed no significant change in the TH level of the E group, which may be because exercise does not cause a noticeable change in the number of neurons. Compared with the St group, both the E and ET groups showed improved motor function (P < 0.01). The results showed that compared with the St group, the protein and gene expression levels of Wnt1, Lmx1a, and Neurog2 were significantly increased in the E, T, and ET groups (P < 0.05). Compared with the T and E groups, the protein and gene expression levels of Wnt1, Lmx1a, and Neurog2 were significantly increased in the ET group (P < 0.05).

CONCLUSION

Exercise increases EPI levels, activates the Wnt signaling pathway through β2 receptors, enhances the Wnt1-Lmx1a regulatory loop, and promotes the differentiation of iPSCs into dopaminergic neurons, thereby increasing the number of neurons.

Keywords: Parkinson’s disease; Induced pluripotent stem cells; Epinephrine; Wnt1; Lmx1a; Exercise

Core Tip: This study explores the combined therapeutic effect of exercise and induced pluripotent stem cells (iPSCs) in a Parkinson’s disease mouse model. Exercise alone enhances motor function and activates the Wnt signaling pathway, increasing adrenaline and Wnt1 levels. Combining exercise with iPSC treatment further boosts the Wnt1-Lmx1a regulatory loop, promoting iPSC differentiation into dopaminergic neurons and significantly improving motor function.