Basic Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Sep 26, 2022; 14(9): 729-743
Published online Sep 26, 2022. doi: 10.4252/wjsc.v14.i9.729
Intercellular mitochondrial transfer as a means of revitalizing injured glomerular endothelial cells
Li-Xia Tang, Bing Wei, Lu-Yao Jiang, You-You Ying, Ke Li, Tian-Xi Chen, Ruo-Fei Huang, Miao-Jun Shi, Hang Xu
Li-Xia Tang, You-You Ying, Ke Li, Ruo-Fei Huang, Department of Endocrinology, The First People’s Hospital of Yongkang Affiliated to Hangzhou Medical College, Jinhua 321300, Zhejiang Province, China
Bing Wei, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
Lu-Yao Jiang, Department of Medical Rehabilitation, The First People’s Hospital of Yongkang Affiliated to Hangzhou Medical College, Jinhua 321300, Zhejiang Province, China
Tian-Xi Chen, Miao-Jun Shi, Department of Nephrology, The First People’s Hospital of Yongkang Affiliated to Hangzhou Medical College, Jinhua 321300, Zhejiang Province, China
Hang Xu, Department of Hemodialysis/Nephrology, The First People’s Hospital of Yongkang Affiliated to Hangzhou Medical College, Jinhua 321300, Zhejiang Province, China
Author contributions: Tang LX, Wei B, Li K, and Xu H designed the study; Tang LX and Wei B wrote the manuscript; Tang LX, Wei B, Jiang LY, Ying YY, Chen TX, Huang RF, and Shi MJ performed the experiments; Tang LX, Wei B, Li K, and Xu H analysed the data; and all authors have read and approved the final manuscript.
Supported by the Science and Technology Foundation of Jinhua, No. 2021-4-190.
Institutional animal care and use committee statement: The animal experiments were carried out following the National Institutes of Health Guidelines for the care and use of laboratory animals and according to protocols approved by the Animal Experimental Ethical Committee of Southeast University (Nanjing, China). The animals were acclimatized to laboratory conditions (22-25 °C, 12 h/12 h light/dark, 50% humidity, ad libitum access to food and water). All animals were euthanized by 2%-3% halothane and then carbon dioxide inhalation for kidney tissue collection.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The datasets supporting the conclusions of this article are included within the article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
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: Hang Xu, BMed, Doctor, Occupational Physician, Department of Hemodialysis/Nephrology, The First People’s Hospital of Yongkang Affiliated to Hangzhou Medical College, No. 599, Jinshan West Road, Dongcheng District, Jinhua 321300, Zhejiang Province, China. 13758989843@163.com
Received: May 23, 2022
Peer-review started: May 23, 2022
First decision: July 6, 2022
Revised: July 18, 2022
Accepted: September 6, 2022
Article in press: September 6, 2022
Published online: September 26, 2022
Processing time: 123 Days and 8.3 Hours
Abstract
BACKGROUND

Recent studies have demonstrated that mesenchymal stem cells (MSCs) can rescue injured target cells via mitochondrial transfer. However, it has not been fully understood how bone marrow-derived MSCs repair glomeruli in diabetic kidney disease (DKD).

AIM

To explore the mitochondrial transfer involved in the rescue of injured glomerular endothelial cells (GECs) by MSCs, both in vitro and in vivo.

METHODS

In vitro experiments were performed to investigate the effect of co-culture with MSCs on high glucose-induced GECs. The transfer of mitochondria was visualized using fluorescent microscopy. GECs were freshly sorted and ultimately tested for apoptosis, viability, mRNA expression by real-time reverse transcriptase-polymerase chain reaction, protein expression by western blot, and mitochondrial function. Moreover, streptozotocin-induced DKD rats were infused with MSCs, and renal function and oxidative stress were detected with an automatic biochemical analyzer and related-detection kits after 2 wk. Kidney histology was analyzed by hematoxylin and eosin, periodic acid-Schiff, and immunohistochemical staining.

RESULTS

Fluorescence imaging confirmed that MSCs transferred mitochondria to injured GECs when co-cultured in vitro. We found that the apoptosis, proliferation, and mitochondrial function of injured GECs were improved following co-culture. Additionally, MSCs decreased pro-inflammatory cytokines [interleukin (IL)-6, IL-1β, and tumor necrosis factor-α] and pro-apoptotic factors (caspase 3 and Bax). Mitochondrial transfer also enhanced the expression of superoxide dismutase 2, B cell lymphoma-2, glutathione peroxidase (GPx) 3, and mitofusin 2 and inhibited reactive oxygen species (ROS) and dynamin-related protein 1 expression. Furthermore, MSCs significantly ameliorated functional parameters (blood urea nitrogen and serum creatinine) and decreased the production of malondialdehyde, advanced glycation end products, and ROS, whereas they increased the levels of GPx and superoxide dismutase in vivo. In addition, significant reductions in the glomerular basement membrane and renal interstitial fibrosis were observed following MSC treatment.

CONCLUSION

MSCs can rejuvenate damaged GECs via mitochondrial transfer. Additionally, the improvement of renal function and pathological changes in DKD by MSCs may be related to the mechanism of mitochondrial transfer.

Keywords: Mitochondria transfer, Mesenchymal stem cells, Glomerular endothelial cells, Diabetic kidney disease, Mitochondrial dysfunction, Oxidative stress

Core Tip: This study demonstrated that the MitoTracker Red CMXRos labeled mitochondria were transferred from mesenchymal stem cells (MSCs) to the high glucose-injured glomerular endothelial cells (GECs) in vitro. Additionally, GEC proliferation was enhanced, and GEC apoptosis was suppressed. Furthermore, in vivo experiments showed that MSCs ameliorated renal function damage and pathological progression of diabetic kidney disease (DKD). These data suggest that MSCs may rescue damaged GECs and improve the renal function and pathological changes of DKD partly through mitochondrial transfer.