High glucose microenvironment and human mesenchymal stem cell behavior

Newswise — 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.

• Citation: Mateen MA, Alaagib N, Haider KH. High glucose microenvironment and human mesenchymal stem cell behavior. World J Stem Cells 2024; 16(3): 237-244
• URL: https://www.wjgnet.com/1948-0210/full/v16/i3/237.htm
• DOI: https://dx.doi.org/10.4252/wjsc.v16.i3.237