Extracellular vesicles derived from human amniotic fluid stem cells improve bladder dysfunction in rat model of diabetic atherosclerosis

doi:10.4252/wjsc.v18.i1.113614

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Jan 26, 2026 (publication date) through Jan 26, 2026

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World Journal of Stem Cells

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1948-0210

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World J Stem Cells. Jan 26, 2026; 18(1): 113614
Published online Jan 26, 2026. doi: 10.4252/wjsc.v18.i1.113614

Extracellular vesicles derived from human amniotic fluid stem cells improve bladder dysfunction in rat model of diabetic atherosclerosis

Ching-Chung Liang, Yi-Hao Lin, Chu-Ya Liang, Aileen Ro, Yung-Hsin Huang, Steven W Shaw

Ching-Chung Liang, Yi-Hao Lin, Aileen Ro, Yung-Hsin Huang, Female Urology Section, Department of Obstetrics and Gynecology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan

Ching-Chung Liang, Yi-Hao Lin, Steven W Shaw, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan

Chu-Ya Liang, Graduate Institute of Management, Chang Gung University, Taoyuan 333, Taoyuan, Taiwan

Steven W Shaw, Division of Obstetrics, Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei 105, Taiwan

Steven W Shaw, Prenatal Cell and Gene Therapy Group, Institute for Women’s Health, University College London, London WC1N 1EH, United Kingdom

Author contributions: Liang CC, Lin YH, and Shaw SW designed the study; Liang CC and Shaw SW were responsible for obtaining funds; Liang CC, Huang YH, and Shaw SW collected tissue samples; Liang CC, Liang CY, and Huang YH contributed new reagents and analytic tools; Lin YH, Liang CY, and Huang YH performed the research; Liang CC, Liang CY, Ro A, and Shaw SW analyzed the data and wrote the manuscript; and all authors read and approved the final manuscript.

Supported by the Ministry of Science and Technology Taiwan, No. MOST 109-2314-B-182A-091, No. NSTC 112-2314-B-182A-062, and No. NSTC 113-2314-B-182A-125.

Institutional review board statement: The study was reviewed and approved by the Institutional Review Board of Linkou Chang Gung Memorial Hospital (No. 201902019A3).

Institutional animal care and use committee statement: The present work was approved by the Institutional Ethics Committee for the Care and Use of Experimental Animals of Chang Gung Memorial Hospital (No. 2019121712).

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: No additional data are available.

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: Steven W Shaw, MD, PhD, Professor, Division of Obstetrics, Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, No. 199 Dunhua North Road, Taipei 105, Taiwan. doctor.obsgyn@gmail.com

Received: September 1, 2025
Revised: October 6, 2025
Accepted: November 26, 2025
Published online: January 26, 2026
Processing time: 143 Days and 21.3 Hours

Abstract

BACKGROUND

The incidence of diabetic atherosclerosis (DMA) is increasing worldwide, but its pathogenesis remains incompletely understood. In addition to cardiovascular complications, bladder dysfunction is one of the common comorbidities associated with DMA but is often refractory to current treatments.

AIM

To investigate the therapeutic effect of human amniotic fluid stem cell-derived extracellular vesicles (hAFSC-EVs) on the recovery of bladder dysfunction in DMA rats.

METHODS

Eighty rats were divided into normal control, streptozotocin-induced diabetic rats, diabetic rats subjected to arterial balloon endothelial injury of common iliac artery (DMA), and DMA rats treated with hAFSC-EVs (DMA + hAFSC-EVs). At 4 weeks and 12 weeks after DMA induction, levels of blood glucose, total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, homeostasis model assessment (HOMA)-insulin resistance, and HOMA-β were measured. Cystometry, common iliac artery wall thickness, and bladder tumor necrosis factor (TNF)-α, interleukin (IL)-6, transforming growth factor (TGF)-β1, Smad3, connective tissue growth factor (CTGF) and fibronectin were also evaluated.

RESULTS

Bladder weight and blood glucose, triglyceride, HOMA-insulin resistance, common iliac artery intima thickness, voided volume, intercontraction interval, bladder capacity, and mRNA expression of TNF-α, IL-6, TGF-β1, Smad3, CTGF and fibronectin were significantly increased at 4 weeks and 12 weeks after induction, while the HOMA-β level decreased at 4 weeks and 12 weeks, and the high-density lipoprotein cholesterol level decreased at 12 weeks. hAFSC-EVs treatment in DMA rats significantly reduced bladder weight and blood glucose, thickness of common iliac arterial intima, voided volume, intercontraction interval and bladder capacity at 4 weeks. The mRNA expression of TNF-α, TGF-β1, and CTGF in DMA rats treated with hAFSC-EVs were significantly decreased at 4 weeks, while the mRNA expressions of IL-6 and Smad3 were significantly decreased 12 weeks.

CONCLUSION

hAFSC-EVs treatment can help restore DMA-induced bladder dysfunction, which is associated with lowered blood glucose levels, reduced arterial wall thickness, and decreased TNF-α, IL-6, TGF-β1, Smad3, and CTGF expression.

Keywords: Atherosclerosis; Bladder; Diabetes; Exosome; Extracellular vesicles; Stem cell

Core Tip: In addition to cardiovascular complications, bladder dysfunction is one of the common comorbidities associated with diabetes, but is often refractory to current treatments. Human amniotic fluid stem cells (hAFSCs) demonstrated the efficacy in preclinical studies of diabetic bladder dysfunction and arterial atherosclerosis-induced bladder dysfunction. Here, we demonstrate that extracellular vesicles derived from hAFSCs could help restore diabetic atherosclerosis-induced bladder dysfunction, which is associated with lowered blood glucose levels, reduced arterial wall thickness, and decreased tumor necrosis factor-α, interleukin-6, transforming growth factor-β1, Smad3, and connective tissue growth factor expression. Our study highlights the potential of extracellular vesicles derived from hAFSCs in cell-free regenerative therapy of diabetic atherosclerosis.