High glucose microenvironment and human mesenchymal stem cell behavior

Table 1 Summary of some studies from the published literature reporting the effect of high glucose culture conditions

Ref.	Cell type and source	Glucose concentration used	Mechanism	Findings
Zhang et al[19], 2016	Rat BM-MSCs	HG: 16.5 mM vs NG: 5.5 mM	Activation of GSK3β and suppression of CXCR-4, β-catenin, LEF-1, and cyclin D1 under HG culture conditions	The study related HG culture with the activation of GSK3β to affect the proliferation and migration of BM-MSCs in HG culture. The proliferation and migration ability of the cells were suppressed in HG culture. HG activated GSK3β but suppressed CXCR-4, β-catenin, LEF-1, and cyclin D1. Inhibition of GSK3β by lithium chloride led to increased levels of β-catenin, LEF-1, cyclin D1, and CXCR-4 expression
Abu-El-Rub et al[20], 2023	hAD-MSCs	HG: 25 mM vs NG: 5.5 mM	Altered mitochondrial membrane potential, Low NAD+/NADH pool, reduced mTOR and PI3K	HG culture for 7 d showed reduced cell viability compared to NG cultured control. HG culture significantly reduced the mitochondrial membrane potential and NAD+/NADH ratio, showing dysregulated mitochondrial function. PI3K protein expression significantly decreased in HG-cultured cells MSCs with increased TSC1 and downregulation of mTOR protein. Mitochondrial complexes I, IV, and V were reduced in HG, leading to poor survival of MSCs in HG
Li et al[37], 2007	Human BM-MSCs	HG: 25 mM vs NG: 5.6 mM	Molecular mechanism not explored	The effect of HG culture on human MSC in vitro was assessed using telomerase-immortalized MSC (hMSC-TERT) and primary MSC (hMSC). HG increased hMSC-TERT proliferation in long-term studies, while it remained unchanged for hMSCs. Apoptosis was not influenced by HG in both cell types. Moreover, HG culture conditions supported osteogenic differentiation of the cells
Hankamolsiri et al[40], 2016	Human BM-MSCs and MSCs from gestational tissues	HG: 25 mM vs NG: 5.5 mM	HG-induced the expression of adipogenic gene PPARγ and LPL in BM-MSCs, as well as ADIPOQ and LPL genes in gestational tissue-derived MSCs	No change in surface markers’ expression. HG reduced proliferation but enhanced adipogenic differentiation of all MSCs examined. The expression of some adipogenic genes were also upregulated when MSCs were cultured in HG. Although HG transiently reduced some osteogenic genes, its effect on the osteogenic differentiation rate of the MSCs was not demonstrated
Al-Qarakhli et al[41], 2019	Rat BM-MSCs	HG: 25 mM vs NG: 5.5 mM	HG culture conditions significantly reduced telomere length at 50 PDs and 100 PDs. Also attribute it to IGFs, TGF-β1, and BMPs	HG and NG cultured cells had similar morphology and growth characteristics. HG-cultured cells proliferated beyond 50 doublings, although with signs of senescence. The osteogenic and adipogenic differentiation rates were significantly reduced in HG-cultured cells. The effect of HG was more pronounced in advanced PDs
Khasawneh et al[42], 2023	Human AD-MSCs	HG: 25 mM vs NG: 5.5 mM	Reduced AMPK and PFK-1	Immunomodulation potential was lost in the hAD-MSCs under HG conditions and were detectable by immune cells. These changes were mediated by low IDO, IL-10, and complement factor H. AMPK and PFK-1, integral glycolysis regulators, were reduced in HG-cultured MSCs. These findings show the possibility of an immunomodulatory shift in MSCs under HG, leading to poor survival of the cells

ADIPOQ: Adiponectin; AMPK: AMP-activated protein kinase; BM: Bone marrow; BMP: Bone morphogenic proteins; CXCR4: C-X-C chemokine receptor type 4; GSK-3β: Glycogen synthase kinase-3β; hAD-MSCs: Human adipose tissue-derived mesenchymal stem cells; HG: High glucose; IDO: Indoleamine 2,3-dioxygenase; IGF: Insulin-like growth factor; IL: Interleukin; LEF-1: Lymphoid enhancer binding factor-1; LPL: Lipoprotein lipase; MSC: Mesenchymal stem cell; mTOR: Mammalian target of rapamycin; NAD: Nicotinamide adenine dinucleotide; NG: Normal glucose; PD: Population doubling; PFK-1: Phosphofructokinase-1; PI3K: Phosphoinositide 3-kinase; PPARγ: Peroxisome proliferator-activated receptor gamma; TGF-β1: Transforming growth factor-β1; TSC1: Tuberous sclerosis 1.