Ahmed Sara M, Elkhenany Hoda A, Ahmed Toka A, Ghoneim Nehal I, Elkodous Mohamed Abd, Mohamed Rania Hassan, Magdeldin Sameh, Osama Aya, Anwar Ali Mostafa, Gabr Mahmoud M, El-Badri Nagwa
Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Sheikh Zayed District, 6th of October City , 12582, Giza, Egypt.
Department of surgery, Faculty of Veterinary Medicine, Alexandria University, Alexandria, Egypt.
Diabetol Metab Syndr. 2024 Jun 16;16(1):131. doi: 10.1186/s13098-024-01365-1.
Type 2 diabetes is an endocrine disorder characterized by compromised insulin sensitivity that eventually leads to overt disease. Adipose stem cells (ASCs) showed promising potency in improving type 2 diabetes and its complications through their immunomodulatory and differentiation capabilities. However, the hyperglycaemia of the diabetic microenvironment may exert a detrimental effect on the functionality of ASCs. Herein, we investigate ASC homeostasis and regenerative potential in the diabetic milieu.
We conducted data collection and functional enrichment analysis to investigate the differential gene expression profile of MSCs in the diabetic microenvironment. Next, ASCs were cultured in a medium containing diabetic serum (DS) or normal non-diabetic serum (NS) for six days and one-month periods. Proteomic analysis was carried out, and ASCs were then evaluated for apoptosis, changes in the expression of surface markers and DNA repair genes, intracellular oxidative stress, and differentiation capacity. The crosstalk between the ASCs and the diabetic microenvironment was determined by the expression of pro and anti-inflammatory cytokines and cytokine receptors.
The enrichment of MSCs differentially expressed genes in diabetes points to an alteration in oxidative stress regulating pathways in MSCs. Next, proteomic analysis of ASCs in DS revealed differentially expressed proteins that are related to enhanced cellular apoptosis, DNA damage and oxidative stress, altered immunomodulatory and differentiation potential. Our experiments confirmed these data and showed that ASCs cultured in DS suffered apoptosis, intracellular oxidative stress, and defective DNA repair. Under diabetic conditions, ASCs also showed compromised osteogenic, adipogenic, and angiogenic differentiation capacities. Both pro- and anti-inflammatory cytokine expression were significantly altered by culture of ASCs in DS denoting defective immunomodulatory potential. Interestingly, ASCs showed induction of antioxidative stress genes and proteins such as SIRT1, TERF1, Clusterin and PKM2.
We propose that this deterioration in the regenerative function of ASCs is partially mediated by the induced oxidative stress and the diabetic inflammatory milieu. The induction of antioxidative stress factors in ASCs may indicate an adaptation mechanism to the increased oxidative stress in the diabetic microenvironment.
2型糖尿病是一种内分泌紊乱疾病，其特征为胰岛素敏感性受损，最终导致显性疾病。脂肪干细胞（ASC）通过其免疫调节和分化能力，在改善2型糖尿病及其并发症方面显示出有前景的潜力。然而，糖尿病微环境的高血糖可能对ASC的功能产生有害影响。在此，我们研究糖尿病环境中ASC的稳态和再生潜力。
我们进行了数据收集和功能富集分析，以研究糖尿病微环境中MSC的差异基因表达谱。接下来，将ASC在含有糖尿病血清（DS）或正常非糖尿病血清（NS）的培养基中培养6天和1个月。进行蛋白质组学分析，然后评估ASC的凋亡、表面标志物和DNA修复基因表达的变化、细胞内氧化应激以及分化能力。通过促炎和抗炎细胞因子及细胞因子受体的表达来确定ASC与糖尿病微环境之间的相互作用。
糖尿病中MSC差异表达基因的富集表明MSC中氧化应激调节途径发生改变。接下来，对DS中的ASC进行蛋白质组学分析，发现差异表达的蛋白质与细胞凋亡增强、DNA损伤和氧化应激、免疫调节和分化潜能改变有关。我们的实验证实了这些数据，并表明在DS中培养的ASC发生凋亡、细胞内氧化应激和DNA修复缺陷。在糖尿病条件下，ASC的成骨、成脂和血管生成分化能力也受损。DS中ASC的培养显著改变了促炎和抗炎细胞因子的表达，表明免疫调节潜能缺陷。有趣的是，ASC显示出抗氧化应激基因和蛋白质如SIRT1、TERF1、Clusterin和PKM2的诱导。
我们提出，ASC再生功能的这种恶化部分是由诱导的氧化应激和糖尿病炎症环境介导的。ASC中抗氧化应激因子的诱导可能表明是对糖尿病微环境中氧化应激增加的一种适应机制。
