Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, 1-1370 Okamoto, Kamakura 2478533, Japan.
Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, 1-1370 Okamoto, Kamakura 2478533, Japan.
Cells. 2024 Aug 12;13(16):1335. doi: 10.3390/cells13161335.
Under vasculogenic conditioning, certain pro-inflammatory subsets within peripheral blood mononuclear cells (PBMCs) undergo phenotypic transformation into pro-regenerative types, such as vasculogenic endothelial progenitor cells, M2 macrophages, and regulatory T cells. These transformed cells are collectively termed regeneration-associated cells (RACs). In this study, we aimed to investigate the therapeutic efficacy of RAC-derived extracellular vesicles (RACev) compared with a vehicle-treated group in the context of renal ischemia-reperfusion injury (R-IRI). Human PBMCs were cultured with defined growth factor cocktails for seven days to harvest RACs. EV quantity and size were characterized by nanoparticle tracking analysis. Notably, the systemic injection of RACev significantly decreased serum creatinine and blood urine nitrogen at day three compared to the control group. Histologically, the treatment group showed less fibrosis in the cortex and medullary areas ( < 0.04 and < 0.01) compared to the control group. The CD31 staining confirmed enhanced capillary densities in the treatment group compared to the control group ( < 0.003). These beneficial effects were accompanied by angiogenesis, anti-fibrosis, anti-inflammation, and anti-apoptosis RACev miR delivery to ischemic injury to control inflammatory, endothelial mesenchymal transition, and hypoxia pathways. In vivo bioluminescence analysis demonstrated a preferential accumulation of RACev in the IR-injured kidney. The systemic transplantation of RACev beneficially restored kidney function by protecting from tissue fibrosis and through anti-inflammation, angiogenesis, and anti-apoptosis miR delivery to the ischemic tissue.
在血管生成条件作用下，外周血单个核细胞（PBMCs）中的某些促炎亚群经历表型转化为促再生类型，如血管生成内皮祖细胞、M2 巨噬细胞和调节性 T 细胞。这些转化细胞统称为与再生相关的细胞（RACs）。在这项研究中，我们旨在研究 RAC 衍生的细胞外囊泡（RACev）与 vehicle 处理组在肾缺血再灌注损伤（R-IRI）背景下的治疗效果。用人 PBMCs 用特定的生长因子鸡尾酒培养七天以收获 RACs。通过纳米颗粒跟踪分析对 EV 数量和大小进行了表征。值得注意的是，与对照组相比，RACev 的全身注射在第 3 天显著降低了血清肌酐和血尿氮。组织学上，与对照组相比，治疗组皮质和髓质区域的纤维化程度较低（<0.04 和 <0.01）。与对照组相比，CD31 染色证实治疗组的毛细血管密度增加（<0.003）。这些有益的效果伴随着血管生成、抗纤维化、抗炎和抗细胞凋亡 RACev miR 传递到缺血性损伤以控制炎症、内皮间质转化和缺氧途径。体内生物发光分析表明，RACev 优先在 IR 损伤的肾脏中积累。RACev 的全身移植通过保护组织纤维化以及通过向缺血组织传递抗炎、血管生成和抗细胞凋亡 miR，有益地恢复了肾功能。
