Wang Jiao, Liu Honghong, Yue Guanru, Deng Yuanyuan, Cai Wei, Xu Jixiong
Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, China.
Jiangxi Clinical Research Center for Endocrine and Metabolic Disease, Nanchang, China.
Diabetes Obes Metab. 2024 Jan;26(1):32-45. doi: 10.1111/dom.15282. Epub 2023 Sep 18.
To investigate the therapeutic effects and immunomodulatory mechanisms of human placenta-derived mesenchymal stem cells (PMSCs) in diabetic kidney disease (DKD).
Streptozotocin-induced DKD rats were administered an equivalent volume of saline or PMSCs (1 × 10 in 2 mL phosphate-buffered saline per rat) for 3 weeks. Eight weeks after treatment, we examined the biochemical parameters in the blood and urine, the ratio of T helper 17 cells (Th17) and regulatory T cells (Treg) in the blood, cytokine levels in the kidney and blood, and renal histopathological changes. In addition, we performed PMSC tracing and renal transcriptomic analyses using RNA-sequencing. Finally, we determined whether PMSCs modulated the Th17/Treg balance by upregulating programmed death 1 (PD-1) in vitro.
The PMSCs significantly improved renal function, which was assessed by serum creatinine levels, urea nitrogen, cystatin C levels, urinary albumin-creatinine ratio, and the kidney index. Further, PMSCs alleviated pathological changes, including tubular vacuolar degeneration, mesangial matrix expansion, and glomerular filtration barrier injury. In the DKD rats in our study, PMSCs were mainly recruited to immune organs, rather than to the kidney or pancreas. PMSCs markedly promoted the Th17/Treg balance and reduced the levels of pro-inflammatory cytokines (interleukin [IL]-17A and IL-1β) in the kidney and blood of DKD rats. In vitro experiments showed that PMSCs significantly reduced the proportion of Th17 cells and increased the proportion of Treg cells by upregulating PD-1 in a cell-cell contact manner and downregulating programmed death-ligand 1 (PD-L1) expression in PMSCs, which reversed the Th17/Treg balance.
We found that PMSCs improved renal function and pathological damage in DKD rats and modulated Th17/Treg balance through the PD-1/PD-L1 pathway. These findings provide a novel mechanism and basis for the clinical use of PMSCs in the treatment of DKD.
探讨人胎盘间充质干细胞（PMSCs）对糖尿病肾病（DKD）的治疗作用及免疫调节机制。
将链脲佐菌素诱导的DKD大鼠分为两组，分别给予等体积的生理盐水或PMSCs（每只大鼠2 mL磷酸盐缓冲液中含1×10个细胞），连续给药3周。治疗8周后，检测血液和尿液中的生化参数、血液中辅助性T细胞17（Th17）和调节性T细胞（Treg）的比例、肾脏和血液中的细胞因子水平以及肾脏组织病理学变化。此外，我们使用RNA测序进行了PMSCs追踪和肾脏转录组分析。最后，我们在体外确定PMSCs是否通过上调程序性死亡1（PD-1）来调节Th17/Treg平衡。
PMSCs显著改善了肾功能，通过血清肌酐水平、尿素氮、胱抑素C水平、尿白蛋白-肌酐比值和肾脏指数进行评估。此外，PMSCs减轻了病理变化，包括肾小管空泡变性、系膜基质扩张和肾小球滤过屏障损伤。在我们研究的DKD大鼠中，PMSCs主要被募集到免疫器官，而非肾脏或胰腺。PMSCs显著促进了Th17/Treg平衡，并降低了DKD大鼠肾脏和血液中促炎细胞因子（白细胞介素[IL]-17A和IL-1β）的水平。体外实验表明，PMSCs通过细胞间接触方式上调PD-1并下调PMSCs中程序性死亡配体1（PD-L1）的表达，显著降低了Th17细胞的比例，增加了Treg细胞的比例，从而逆转了Th17/Treg平衡。
我们发现PMSCs改善了DKD大鼠肾功能和病理损伤，并通过PD-1/PD-L1途径调节Th17/Treg平衡。这些发现为PMSCs临床治疗DKD提供了新的机制和依据。
