Mesenchymal stem cells therapy ameliorates esophageal dysmotility in gastroesophageal reflux disease by modulating smooth muscle contractility, alleviating senescence by targeting the DNMT3a-HIF1α axis

doi:10.4252/wjsc.120831

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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): 120831
Published online Aug 26, 2026. doi: 10.4252/wjsc.120831

Mesenchymal stem cells therapy ameliorates esophageal dysmotility in gastroesophageal reflux disease by modulating smooth muscle contractility, alleviating senescence by targeting the DNMT3a-HIF1α axis

En-Qiang Linghu, Qian-Qian Chen, Zhao-Yang Chen, Ze-Rui Wang, Bo Zhang, Wen-Ya Zhu, Yi Li

Yi Li, Bo Zhang, Ze-Rui Wang, Qian-Qian Chen, En-Qiang Linghu, Department of Gastroenterology, The First Medical Center, General Hospital of the Chinese PLA, Beijing 100853, China

Wen-Ya Zhu, Department of Gastroenterology, The Six Medical Center, General Hospital of the Chinese PLA, Beijing 100037, China

Zhao-Yang Chen, Department of Emergency, The Six Medical Center, General Hospital of the Chinese PLA, Beijing 100037, China

Co-first authors: Yi Li and Wen-Ya Zhu.

Co-corresponding authors: Qian-Qian Chen, En-Qiang Linghu.

Author contributions: Li Y and Linghu EQ contributed to conceptualization and design; Li Y, Zhu WY, Wang ZR, Zhang B, Chen ZY, Chen QQ, and Linghu EQ contributed to performance of research; Li Y and Zhu WY contributed to data analysis and interpretation and manuscript writing; Zhu WY, Wang ZR, Chen QQ, and Linghu EQ contributed to critical revision of manuscript. Chen QQ and Linghu EQ contributed to supervision, project administration and funding acquisition. Li Y and Zhu WY are co-first authors. They contributed equally to this work, playing irreplaceable roles in distinct phases of the experiments and sharing primary responsibility for data acquisition and manuscript drafting. Chen QQ and Linghu EQ are co-corresponding authors. They contributed equally by securing funding and providing overall supervision and leadership in the study design. All authors have read and approved the final manuscript and take full responsibility for the integrity of the work.

AI contribution statement: After completing the initial draft, we did use the AI tool (gemini-2.5-flash-nothink) for English language polishing. Its primary purpose was to check for grammatical errors, correct spelling, improve sentence fluency, and align academic expressions with international journal conventions. In this process, no scientific facts, data, or logic were altered.

Supported by China Postdoctoral Science Foundation, No. 2020TQ0131; and the Natural Science Foundation of Beijing Municipality, No. 7232151.

Institutional review board statement: The study was approved by the Institutional Review Board of the Chinese PLA General Hospital (No. S2021-052-02).

Institutional animal care and use committee statement: All animal experiments were approved by the Experimental Animal Management Group of Beijing Shenrui Biotechnology Co., Ltd (No. SRSW-DWLL-2022-0820).

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 supporting the findings of this study are available within the article and its Supplementary material. Raw sequencing data are available from the En-Qiang Linghu upon reasonable request.

Corresponding author: En-Qiang Linghu, Department of Gastroenterology, The First Medical Center, General Hospital of the Chinese PLA, No. 28 Fuxing Road, Haidian District, Beijing 100853, China. linghuenqiang@vip.sina.com

Received: March 13, 2026
Revised: April 7, 2026
Accepted: June 3, 2026
Published online: August 26, 2026
Processing time: 160 Days and 18.8 Hours

Abstract

BACKGROUND

Gastroesophageal reflux disease (GERD) is associated with esophageal dysmotility, leading to impaired acid clearance and persistent symptoms. Mesenchymal stem cell (MSC) therapy holds promise for tissue regeneration and functional restoration.

AIM

To investigate the therapeutic efficacy and underlying molecular mechanisms of MSC treatment on esophageal dysmotility in a rat model of GERD and in human esophageal smooth muscle cells (HESMCs).

METHODS

A rat model of chronic GERD was established surgically. Rats were treated with human umbilical cord-derived MSCs via combined intravenous and local injection. Esophageal contractility was measured ex vivo. HESMCs were used for in vitro studies, including a senescence model induced by tumor necrosis factor (TNF)-α and MSC co-culture. Assessments included histology, senescence-associated β-galactosidase staining, immunohistochemistry, western blotting, intracellular Ca²⁺ imaging, small interfering RNA-mediated knockdown, and transcriptomic sequencing.

RESULTS

In vivo, GERD rats exhibited significantly reduced esophageal contractility, increased cellular senescence (β-galactosidase positivity), elevated TNF-α, decreased interleukin-10, and dysregulated expression of smooth muscle contraction-related proteins (decreased myosin light chain kinase, increased myosin phosphatase target subunit 1) and Ca²⁺ channels (decreased CACNA1C). MSC treatment restored esophageal contractility, mitigated senescence, normalized inflammatory markers, and reversed the protein dysregulation. In vitro, MSC co-culture effectively counteracted TNF-α-accelerated senescence in HESMCs, upregulated contractile proteins and ion channels (anoctamin 1, calcium voltage-gated channel subunit alpha1 C), and enhanced intracellular Ca²⁺ concentration. Mechanistically, MSCs modulated DNA methyltransferase 3a (DNMT3a) and hypoxia-inducible factor 1 alpha (HIF1α) pathways; inhibition of DNMT3a suppressed HIF1α, while HIF1α overexpression upregulated contractile proteins, establishing an MSC-DNMT3a-HIF1α axis. Transcriptomic analysis confirmed global gene expression changes in GERD and highlighted MSC-mediated modulation of inflammatory, signaling, and muscle-related pathways.

CONCLUSION

In conclusion, MSCs offer a potent therapeutic strategy for GERD-associated esophageal dysmotility by restoring smooth muscle function, alleviating senescence, and remodeling molecular pathways, primarily via a novel DNMT3a-HIF1α signaling cascade.

Keywords: Mesenchymal stem cells; Gastroesophageal reflux disease; Esophageal dysmotility; DNA methyltransferase 3a/hypoxia-inducible factor 1 alpha axis

Core Tip: This work shows mesenchymal stem cells (MSCs) restore impaired esophageal contractility and reduce inflammation in gastroesophageal reflux disease by regulating ion channels and smooth muscle proteins. MSCs counteract tumor necrosis factor-α-accelerated cell senescence and dysfunction, with DNA methyltransferase 3a and hypoxia-inducible factor 1 alpha pathways implicated. These results uncover critical mechanisms for MSC-mediated regenerative effects, proposing a promising cell-based therapeutic approach for restoring physiological function in gastroesophageal reflux disease.