Basic Study
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World J Stem Cells. Dec 26, 2023; 15(12): 1093-1103
Published online Dec 26, 2023. doi: 10.4252/wjsc.v15.i12.1093
Human mesenchymal stem cells exhibit altered mitochondrial dynamics and poor survival in high glucose microenvironment
Ejlal Abu-El-Rub, Fatimah Almahasneh, Ramada R Khasawneh, Ayman Alzu'bi, Doaa Ghorab, Rawan Almazari, Huthaifa Magableh, Ahmad Sanajleh, Haitham Shlool, Mohammad Mazari, Noor S Bader, Joud Al-Momani
Ejlal Abu-El-Rub, Fatimah Almahasneh, Ramada R Khasawneh, Ayman Alzu'bi, Rawan Almazari, Huthaifa Magableh, Ahmad Sanajleh, Haitham Shlool, Mohammad Mazari, Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid 21163, Jordan
Doaa Ghorab, Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
Noor S Bader, Joud Al-Momani, Department of Basic Medical Sciences, Yarmouk University, Irbid 21163, Jordan
Author contributions: Abu-El-Rub E conceptualized the study; Abu-El-Rub E, Khasawneh RR, Almazari R, Sanajleh A, Magableh H, Shlool H, Mazari M, Bader NS, and Al-Momani J carried out the experiments; Abu-El-Rub E and Almahasneh F analyzed the data; Abu-El-Rub E, Almahasneh F, Alzu'bi A, and Ghorab D drafted and wrote the manuscript; Abu-El-Rub E and Almahasneh F revised and formatted the content of the manuscript and verified spelling, punctuation and grammatical errors; and all authors have read and approve the final manuscript.
Institutional review board statement: The ethical approval was not needed in this study. The human cell lines used for this study were commercially purchased.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
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: Ejlal Abu-El-Rub, PhD, Assistant Professor, Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid-Shafiq Irshidat Street, Irbid 21163, Jordan. ejlal.abuelrub@yu.edu.jo
Received: September 28, 2023
Peer-review started: September 28, 2023
First decision: October 23, 2023
Revised: November 11, 2023
Accepted: November 24, 2023
Article in press: November 24, 2023
Published online: December 26, 2023
Abstract
BACKGROUND

Mesenchymal stem cells (MSCs) are a type of stem cells that possess relevant regenerative abilities and can be used to treat many chronic diseases. Diabetes mellitus (DM) is a frequently diagnosed chronic disease characterized by hyperglycemia which initiates many multisystem complications in the long-run. DM patients can benefit from MSCs transplantation to curb down the pathological consequences associated with hyperglycemia persistence and restore the function of damaged tissues. MSCs therapeutic outcomes are found to last for short period of time and ultimately these regenerative cells are eradicated and died in DM disease model.

AIM

To investigate the impact of high glucose or hyperglycemia on the cellular and molecular characteristics of MSCs.

METHODS

Human adipose tissue-derived MSCs (hAD-MSCs) were seeded in low (5.6 mmol/L of glucose) and high glucose (25 mmol/L of glucose) for 7 d. Cytotoxicity, viability, mitochondrial dynamics, and apoptosis were deplored using specific kits. Western blotting was performed to measure the protein expression of phosphatidylinositol 3-kinase (PI3K), TSC1, and mammalian target of rapamycin (mTOR) in these cells.

RESULTS

hAD-MSCs cultured in high glucose for 7 d demonstrated marked decrease in their viability, as shown by a significant increase in lactate dehydrogenase (P < 0.01) and a significant decrease in Trypan blue (P < 0.05) in these cells compared to low glucose control. Mitochondrial membrane potential, indicated by tetramethylrhodamine ethyl ester (TMRE) fluorescence intensity, and nicotinamide adenine dinucleotide (NAD+)/NADH ratio were significantly dropped (P < 0.05 for TMRE and P < 0.01 for NAD+/NADH) in high glucose exposed hAD-MSCs, indicating disturbed mitochondrial function. PI3K protein expression significantly decreased in high glucose culture MSCs (P < 0.05 compared to low glucose) and it was coupled with significant upregulation in TSC1 (P < 0.05) and downregulation in mTOR protein expression (P < 0.05). Mitochondrial complexes I, IV, and V were downregulated profoundly in high glucose (P < 0.05 compared to low glucose). Apoptosis was induced as a result of mitochondrial impairment and explained the poor survival of MSCs in high glucose.

CONCLUSION

High glucose impaired the mitochondrial dynamics and regulatory proteins in hAD-MSCs ensuing their poor survival and high apoptosis rate in hyperglycemic microenvironment.

Keywords: Mesenchymal stem cells, High glucose, Mitochondrial dynamics, Apoptosis, Poor survival, Phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway

Core Tip: Mesenchymal stem cells (MSCs) have significant regenerative properties that make them a potential treatment for many chronic diseases. Among these, diabetes mellitus (DM) was found to benefit from MSCs transplantation in which they restored the damaged tissues and prevented hyperglycemia-related complications. However, these therapeutic are short-lived hindering the clinical use of MSCs in the treatment of DM. This study aims to elucidate the mechanisms of hyperglycemia-induced effects on MSCs which will help in improving the therapeutic functions of these cells in this stress environment.