Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, October Gardens, 6th of October City, Giza, 12582, Egypt.
Egypt Center for Research and Regenerative Medicine (ECRRM), Cairo, Egypt.
Stem Cell Res Ther. 2024 Feb 8;15(1):36. doi: 10.1186/s13287-024-03643-1.
Pericytes (PCs) are multipotent contractile cells that wrap around the endothelial cells (ECs) to maintain the blood vessel's functionality and integrity. The hyperglycemia associated with Type 2 diabetes mellitus (T2DM) was shown to impair the function of PCs and increase the risk of diabetes complications. In this study, we aimed to investigate the deleterious effect of the diabetic microenvironment on the regenerative capacities of human PCs.
PCs isolated from human adipose tissue were cultured in the presence or absence of serum collected from diabetic patients. The functionality of PCs was analyzed after 6, 14, and 30 days.
Microscopic examination of PCs cultured in DS (DS-PCs) showed increased aggregate formation and altered surface topography with hyperbolic invaginations. Compared to PCs cultured in normal serum (NS-PCs), DS-PCs showed more fragmented mitochondria and thicker nuclear membrane. DS caused impaired angiogenic differentiation of PCs as confirmed by tube formation, decreased VEGF-A and IGF-1 gene expression, upregulated TSP1, PF4, actin-related protein 2/3 complex, and downregulated COL21A1 protein expression. These cells suffered more pronounced apoptosis and showed higher expression of Clic4, apoptosis facilitator BCl-2-like protein, serine/threonine protein phosphatase, and caspase-7 proteins. DS-PCs showed dysregulated DNA repair genes CDKN1A, SIRT1, XRCC5 TERF2, and upregulation of the pro-inflammatory genes ICAM1, IL-6, and TNF-α. Further, DS-treated cells also showed disruption in the expression of the focal adhesion and binding proteins TSP1, TGF-β, fibronectin, and PCDH7. Interestingly, DS-PCs showed resistance mechanisms upon exposure to diabetic microenvironment by maintaining the intracellular reactive oxygen species (ROS) level and upregulation of extracellular matrix (ECM) organizing proteins as vinculin, IQGAP1, and tubulin beta chain.
These data showed that the diabetic microenvironment exert a deleterious effect on the regenerative capacities of human adipose tissue-derived PCs, and may thus have possible implications on the vascular complications of T2DM. Nevertheless, PCs have shown remarkable protective mechanisms when initially exposed to DS and thus they could provide a promising cellular therapy for T2DM.
周细胞（PCs）是一种多能收缩细胞，包裹在内皮细胞（ECs）周围，以维持血管的功能和完整性。与 2 型糖尿病（T2DM）相关的高血糖被证明会损害 PCs 的功能，并增加糖尿病并发症的风险。在这项研究中，我们旨在研究糖尿病微环境对人 PCs 再生能力的有害影响。
从人脂肪组织中分离出的 PCs 在存在或不存在来自糖尿病患者的血清的情况下进行培养。在第 6、14 和 30 天分析 PCs 的功能。
在 DS 中培养的 PCs（DS-PCs）的显微镜检查显示聚集形成增加，表面形貌发生改变，出现双曲内陷。与在正常血清（NS-PCs）中培养的 PC 相比，DS-PCs 的线粒体更碎片化，核膜更厚。DS 导致 PCs 的血管生成分化受损，这一点通过管形成、VEGF-A 和 IGF-1 基因表达降低、TSP1、PF4、肌动蛋白相关蛋白 2/3 复合物表达上调和 COL21A1 蛋白表达下调得到证实。这些细胞凋亡更为明显，并且 Clic4、凋亡促进因子 BCl-2 样蛋白、丝氨酸/苏氨酸蛋白磷酸酶和半胱天冬酶-7 蛋白表达升高。DS-PCs 中 DNA 修复基因 CDKN1A、SIRT1、XRCC5 TERF2 表达失调，促炎基因 ICAM1、IL-6 和 TNF-α 表达上调。此外，DS 处理的细胞还表现出黏附斑和结合蛋白 TSP1、TGF-β、纤连蛋白和 PCDH7 的表达中断。有趣的是，DS-PCs 在暴露于糖尿病微环境时通过维持细胞内活性氧（ROS）水平和上调细胞外基质（ECM）组织蛋白（如黏着斑蛋白、IQGAP1 和微管蛋白β链）来表现出抵抗机制。
这些数据表明，糖尿病微环境对人脂肪组织来源的 PCs 的再生能力产生有害影响，因此可能对 T2DM 的血管并发症产生影响。然而，PCs 在最初暴露于 DS 时表现出显著的保护机制，因此它们可能为 T2DM 提供有前途的细胞治疗。
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