Mateen MA, Alaagib N, Haider KH. High glucose microenvironment and human mesenchymal stem cell behavior. World J Stem Cells 2024; 16(3): 237-244 [PMID: 38577235 DOI: 10.4252/wjsc.v16.i3.237]
Corresponding Author of This Article
Khawaja Husnain Haider, BPharm, BSc, PhD, Chairman, Full Professor, Professor, Cellular and Molecular Pharmacology, Sulaiman AlRajhi Medical School, PO Box 777, Al Bukairiyah 51941, Saudi Arabia. kh.haider@sr.edu.sa
Research Domain of This Article
Cell Biology
Article-Type of This Article
Editorial
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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: http://creativecommons.org/licenses/by-nc/4.0/
World J Stem Cells. Mar 26, 2024; 16(3): 237-244 Published online Mar 26, 2024. doi: 10.4252/wjsc.v16.i3.237
High glucose microenvironment and human mesenchymal stem cell behavior
Muhammad Abdul Mateen, Nouralsalhin Alaagib, Khawaja Husnain Haider
Muhammad Abdul Mateen, Nouralsalhin Alaagib, Basic Sciences, Sulaiman AlRajhi University, AlQaseem 52736, Saudi Arabia
Khawaja Husnain Haider, Cellular and Molecular Pharmacology, Sulaiman AlRajhi Medical School, Al Bukairiyah 51941, Saudi Arabia
Author contributions: Alaagib N contributed to the apoptosis and supported the visual abstract; Mateen MA was involved in the mitochondrial membrane potential and visual abstract; Haider KH contributed to stem cells and overall write-up; All authors revised the manuscript.
Conflict-of-interest statement: The authors declare that they have no conflicting interests.
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: Khawaja Husnain Haider, BPharm, BSc, PhD, Chairman, Full Professor, Professor, Cellular and Molecular Pharmacology, Sulaiman AlRajhi Medical School, PO Box 777, Al Bukairiyah 51941, Saudi Arabia. kh.haider@sr.edu.sa
Received: December 25, 2023 Peer-review started: December 25, 2023 First decision: January 11, 2024 Revised: January 11, 2024 Accepted: January 29, 2024 Article in press: January 29, 2024 Published online: March 26, 2024 Processing time: 90 Days and 10.6 Hours
Abstract
High glucose (HG) culture conditions in vitro and persistent exposure to hyperglycemia in diabetes patients are detrimental to stem cells, analogous to any other cell type in our body. It interferes with diverse signaling pathways, i.e. mammalian target of rapamycin (mTOR)-phosphoinositide 3-kinase (PI3K)-Akt signaling, to impact physiological cellular functions, leading to low cell survival and higher cell apoptosis rates. While elucidating the underlying mechanism responsible for the apoptosis of adipose tissue-derived mesenchymal stem cells (MSCs), a recent study has shown that HG culture conditions dysregulate mTOR-PI3K-Akt signaling in addition to mitochondrial malfunctioning due to defective mitochondrial membrane potential (MtMP) that lowers ATP production. This organelle-level dysfunction energy-starves the cells and increases oxidative stress and ultrastructural abnormalities. Disruption of the mitochondrial electron transport chain produces an altered mitochondrial NAD+/NADH redox state as evidenced by a low NAD+/NADH ratio that primarily contributes to the reduced cell survival in HG. Some previous studies have also reported altered mitochondrial membrane polarity (causing hyperpolarization) and reduced mitochondrial cell mass, leading to perturbed mitochondrial homeostasis. The hostile microenvironment created by HG exposure creates structural and functional changes in the mitochondria, altering their bioenergetics and reducing their capacity to produce ATP. These are significant data, as MSCs are extensively studied for tissue regeneration and restoring their normal functioning in cell-based therapy. Therefore, MSCs from hyperglycemic donors should be cautiously used in clinical settings for cell-based therapy due to concerns of their poor survival rates and increased rates of post engraftment proliferation. As hyperglycemia alters the bioenergetics of donor MSCs, rectifying the loss of MtMP may be an excellent target for future research to restore the normal functioning of MSCs in hyperglycemic patients.
Core Tip: High glucose (HG) conditions, seen in vitro as well as in diabetic patients, adversely affect stem cells by disrupting mammalian target of rapamycin-phosphoinositide 3-kinase-Akt signaling, resulting in reduced cell survival and increased apoptosis. A recent study of adipose tissue-derived mesenchymal stem cells (MSCs) found dysregulation of this signaling pathway and defective mitochondrial membrane potential (MtMP) under HG conditions. This leads to decreased ATP production, heightened oxidative stress, and structural abnormalities, causing diminished cell survival. Altered mitochondrial NAD+/NADH redox state and disrupted mitochondrial homeostasis worsen the hostile microenvironment induced by HG exposure. These findings are a note of caution for using MSCs from hyperglycemic donors in cell-based therapy owing to their poor survival and proliferation rates. Future research targeting MtMP restoration may enhance the therapeutic efficacy of MSCs in hyperglycemic patients.
