Human amniotic mesenchymal stem cells-derived conditioned medium and exosomes alleviate oxidative stress-induced retinal degeneration by activating PI3K/Akt/FoxO3 pathway

Zhe-Qing Peng; Xiao-Hui Guan; Zhen-Ping Yu; Jie Wu; Xin-Hao Han; Ming-Hui Li; Xin-Hui Qu; Zhi-Ping Chen; Xiao-Jian Han; Xiao-Yu Wang

doi:10.1016/j.exer.2024.109919

Human amniotic mesenchymal stem cells-derived conditioned medium and exosomes alleviate oxidative stress-induced retinal degeneration by activating PI3K/Akt/FoxO3 pathway

Exp Eye Res. 2024 May 8:244:109919. doi: 10.1016/j.exer.2024.109919. Online ahead of print.

Authors

Zhe-Qing Peng¹, Xiao-Hui Guan², Zhen-Ping Yu², Jie Wu³, Xin-Hao Han⁴, Ming-Hui Li¹, Xin-Hui Qu⁵, Zhi-Ping Chen⁴, Xiao-Jian Han⁶, Xiao-Yu Wang⁷

Affiliations

¹ Institute of Geriatrics, Jiangxi Provincial People's Hospital & the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, PR China; Department of Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, Jiangxi, 330006, PR China.
² The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, 330031, PR China.
³ Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, 330052, PR China.
⁴ Institute of Geriatrics, Jiangxi Provincial People's Hospital & the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, PR China.
⁵ Institute of Geriatrics, Jiangxi Provincial People's Hospital & the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, PR China; The Second Department of Neurology, Jiangxi Provincial People's Hospital & the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, PR China.
⁶ Institute of Geriatrics, Jiangxi Provincial People's Hospital & the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, PR China. Electronic address: hanxiaojian@hotmail.com.
⁷ Institute of Geriatrics, Jiangxi Provincial People's Hospital & the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, PR China. Electronic address: wangxy202201@163.com.

PMID: 38729254
DOI: 10.1016/j.exer.2024.109919

Abstract

Age-related macular degeneration (AMD) is the leading cause of vision loss among the elderly, which is primarily attributed to oxidative stress-induced damage to the retinal pigment epithelium (RPE). Human amniotic mesenchymal stem cells (hAMSC) were considered to be one of the most promising stem cells for clinical application due to their low immunogenicity, tissue repair ability, pluripotent potential and potent paracrine effects. The conditional medium (hAMSC-CM) and exosomes (hAMSC-exo) derived from hAMSC, as mediators of intercellular communication, play an important role in the treatment of retinal diseases, but their effect and mechanism on oxidative stress-induced retinal degeneration are not explored. Here, we reported that hAMSC-CM alleviated H₂O₂-induced ARPE-19 cell death through inhibiting mitochondrial-mediated apoptosis pathway in vitro. The overproduction of reactive oxygen species (ROS), alteration in mitochondrial morphology, loss of mitochondrial membrane potential and elevation of Bax/Bcl2 ratio in ARPE-19 cells under oxidative stress were efficiently reversed by hAMSC-CM. Moreover, it was found that hAMSC-CM protected cells against oxidative injury via PI3K/Akt/FoxO3 signaling. Intriguingly, exosome inhibitor GW4869 alleviated the inhibitory effect of hAMSC-CM on H₂O₂-induced decrease in cell viability of ARPE-19 cells. We further demonstrated that hAMSC-exo exerted the similar protective effect on ARPE-19 cells against oxidative damage as hAMSC-CM. Additionally, both hAMSC-CM and hAMSC-exo ameliorated sodium iodate-induced deterioration of RPE and retinal damage in vivo. These results first indicate that hAMSC-CM and hAMSC-exo protect RPE cells from oxidative damage by regulating PI3K/Akt/FoxO3 pathway, suggesting hAMSC-CM and hAMSC-exo will be a promising cell-free therapy for the treatment of AMD in the future.

Keywords: Age-related macular degeneration; Exosomes; Human amniotic mesenchymal stem cells; Intrinsic apoptosis; Oxidative stress; PI3K/Akt/FoxO3 pathway.