Hypoxia-conditioned extracellular vesicles from human amniotic membrane stem cells attenuate D-galactose-induced aging in mice

doi:10.4252/wjsc.v18.i4.117707

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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. Apr 26, 2026; 18(4): 117707
Published online Apr 26, 2026. doi: 10.4252/wjsc.v18.i4.117707

Hypoxia-conditioned extracellular vesicles from human amniotic membrane stem cells attenuate D-galactose-induced aging in mice

Khan-Erdene Tsolmon, Zolzaya Bavuu, Solar Sora Kim, Heon-Sang Jeong, Dongsun Park, Yun-Bae Kim

Khan-Erdene Tsolmon, Zolzaya Bavuu, Yun-Bae Kim, College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Chungbuk, South Korea

Solar Sora Kim, High-Technology Research Institute, ThanEver Inc., Daejeon 34054, South Korea

Heon-Sang Jeong, Department of Food Science and Technology, Chungbuk National University, Cheongju 28644, Chungbuk, South Korea

Dongsun Park, College of Veterinary Medicine, Kangwon National University, Chuncheon 24341, Gangwon, South Korea

Co-first authors: Khan-Erdene Tsolmon and Zolzaya Bavuu.

Author contributions: Tsolmon KE and Bavuu Z performed animal experiments and analyzed brain & muscle tissues, they contributed equally to this manuscript and are co-first authors; Kim SS and Jeong HS prepared extracellular vesicles and analyzed; Park D collected and analyzed data; Kim YB designed and interpreted the study, and wrote the manuscript.

Supported by the Regional Innovation System & Education Global University 30 Program Through the Chungbuk Regional Innovation System & Education Center, No. 2025-RISE-11-014.

Institutional review board statement: All human tissues were obtained with the approval of the Institutional Review Board of Korea University Anam Hospital (Approval No. 2020AN0305).

Institutional animal care and use committee statement: All protocols and procedures of animal experiments complied with the Institutional Animal Care and Use Committee of Chungbuk National University (Approval No. CBNUA-24-0021-01).

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: None data sharing.

Corresponding author: Yun-Bae Kim, PhD, Professor, College of Veterinary Medicine, Chungbuk National University, 1 Chungdaero (Gaesin-dong), Cheongju 28644, Chungbuk, South Korea. solar93@cbu.ac.kr

Received: December 15, 2025
Revised: January 17, 2026
Accepted: March 9, 2026
Published online: April 26, 2026
Processing time: 127 Days and 19.5 Hours

Abstract

BACKGROUND

Anti-aging for the preservation and recovery of physical and brain functions may be a major topic of regenerative medicine in the super-aging society. Stem cells and their secretory active molecules can play a central role of regenerative medicine.

AIM

To investigate whether extracellular vesicles (EVs) from amniotic membrane stem cells (AMSCs) enhance physical activity, including stamina, and cognitive function in a mouse model of facilitated brain-aging, and to elucidate underlying mechanisms.

METHODS

EVs were collected from conditioned media of AMSCs after hypoxic (2% O₂, 5% CO₂) cultivation for 3 days. The size and composition of EVs was analyzed via nanoparticle-tracking analysis and proteome/lipidome profiles, and functional molecules such as growth factors and neurotrophic factors were analyzed via enzyme linked immunosorbent assay. Male ICR mice were subcutaneously administered with D-galactose (300 mg/kg) for 6 weeks to induce facilitated aging, during which intravenously injected with EVs (6 × 10⁸ exosome particles/body) at weeks 0, 2, 4, and 6. Physical activity and cognitive function were assessed through Rota-rod, forced swimming and passive avoidance performances, respectively. To clarify underlying mechanisms, acetylcholine (ACh), brain-derived neurotrophic factor (BDNF), sirtuin 1 (SIRT1), glial fibrillary acid protein (GFAP), glycogen, and thiobarbituric acid-reactive substances (TBARS) were analyzed in the brain and muscles.

RESULTS

Six-week injection of D-galactose decreased physical activity and impaired learning and memory function, along with the reduced ACh, BDNF, SIRT1, and glycogen in the brain and muscles, whereas brain GFAP and muscular TBARS increased. However, EV treatment recovered the D-galactose-induced neurobehavioral deficits not only by increasing BDNF and SIRT1 (regulating neuro-muscular adaptation and function) and enhancing brain ACh (governing memory acquisition), but also by restoring muscular glycogen (an energy source) and attenuating brain GFAP and muscular TBARS (inflammatory and oxidative injury markers).

CONCLUSION

EVs from AMSCs restored cognitive function of mice with facilitated brain-aging by increasing ACh, BDNF, and SIRT1. EVs also enhanced stamina not only by attenuating tissue injury, but also by strengthening the muscles through the production of glycogen and BDNF.

Keywords: Aging; Physical activity; Cognitive function; Amniotic membrane stem cell; Extracellular vesicle; Growth factor; Neurotrophic factor

Core Tip: We obtained a large amount of extracellular vesicles containing high concentrations of growth factors and neurotrophic factors via hypoxic cultivation of amniotic membrane stem cells. The extracellular vesicles ameliorated physical and cognitive dysfunctions by recovering anti-aging factors and energy sources, in the brain and muscles, such as brain-derived neurotrophic factor, sirtuin 1, glycogen, acetylcholine, and antioxidation.