Mesenchymal Stem Cell-Conditioned Medium Improves Mitochondrial Dysfunction and Suppresses Apoptosis in Okadaic Acid-Treated SH-SY5Y Cells by Extracellular Vesicle Mitochondrial Transfer

Article type: Research Article

Authors: Zhang, Zhihua^{a; b; c; 1} | Sheng, Hongxia^{b; c; 1} | Liao, Li^{b; c} | Xu, Chen^{b; c} | Zhang, Ang^{a; b; c} | Yang, Yang^{b; c} | Zhao, Long^{b; c} | Duan, Lian^d | Chen, Hu^{b; c} | Zhang, Bin^{b; c; *}

Affiliations: [a] Academy of Military Medical Sciences, Academy of Military Sciences, Beijing, China | [b] Department of Hematopoietic Stem Cell Transplantation, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China | [c] Beijing Key Laboratory of Stem Cell Therapy and Transformation Research, Beijing, China | [d] Fifth Medical Center of Chinese PLA General Hospital, Beijing, China

Correspondence: [*] Correspondence to: Dr. Bin Zhang, Fifth Medical Center of Chinese PLA General Hospital, ^#8 East Street, Fengtai District, Beijing 100071, China. E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Background:Mesenchymal stem cells-conditioned medium (MSC-CM) provides a promising cell-free therapy for Alzheimer’s disease (AD) mainly due to the paracrine of MSCs, but the precise mechanisms remain unclear. Studies suggests that mitochondrial dysfunction precedes the accumulation of amyloid-β plaques and neurofibrillary tangles, and involves in the onset and development of AD. Objective:In the present study, we evaluated the protective effects and explored the related-mitochondrial mechanisms of human umbilical cord derived MSC-CM (hucMSC-CM) in an AD model in vitro. Methods:To this end, an AD cellular model was firstly established by okadaic acid (OA)-treated SH-SY5Y cells, and then treated by hucMSC-CM to assess the oxidative stress, mitochondrial function, apoptosis, AD-related genes, and signaling pathways. Results:hucMSC-CM significantly deceased tau phosphorylated at Thr181 (p181-tau) level, which was increased in AD. hucMSC-CM also alleviated intracellular and mitochondrial oxidative stress in OA-treated SH-SY5Y cells. In addition, hucMSC-CM suppressed apoptosis and improved mitochondrial function in OA-treated SH-SY5Y cells. Flow cytometric analysis indicated that hucMSC-CM exerted the protective effects relying on or partly extracellular vesicle (EV) mitochondrial transfer from hucMSCs to OA-treated SH-SY5Y cells. Moreover, RNA sequencing data further demonstrated that hucMSC-CM regulated many AD-related genes, signaling pathways and mitochondrial function. Conclusion:These results indicated that MSC-CM or MSC-EVs containing abundant mitochondria may provide a novel potential therapeutic approach for AD.

Keywords: Alzheimer’s disease, apoptosis, mesenchymal stem cell-conditioned medium, mitochondrial dysfunction, mitochondrial transfer

DOI: 10.3233/JAD-200686

Journal: Journal of Alzheimer's Disease, vol. 78, no. 3, pp. 1161-1176, 2020