Lim Sun Woo, Kim Kyung Woon, Kim Bo Mi, Shin Yoo Jin, Luo Kang, Quan Yi, Cui Sheng, Ko Eun Jeong, Chung Byung Ha, Yang Chul Woo
Transplant Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Convergent Research Consortium for Immunologic disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Korean J Intern Med. 2022 Mar;37(2):411-424. doi: 10.3904/kjim.2020.438. Epub 2021 Sep 16.
BACKGROUND/AIMS: Renal ischemia followed by reperfusion (I/R) is a leading cause of acute kidney injury (AKI), which is closely associated with high morbidity and mortality. Studies have shown that induced pluripotent stem cell (iPSC)-derived mesenchymal stem cells (iMSCs) exert powerful therapeutic effects in renal ischemia. However, the efficacy of iMSC-derived exosomes (iExo) on I/R injuries remains largely unknown.
Human iPSCs were differentiated into iMSCs using a modified one-step method. Ultrafiltration, combined with purification, was used to isolate iExo from iMSCs. iExo was administered following I/R injury in a mouse model. The effect of iExo on I/R injury was assessed through changes in renal function, histology, and expression of oxidative stress, inflammation, and apoptosis markers. Further, we evaluated its association with the extracellular signal-regulated kinase (ERK) 1/2 signaling pathway.
Mice subjected to I/R injury exhibited typical AKI patterns; serum creatinine level, tubular necrosis, apoptosis, inflammatory cytokine production, and oxidative stress were markedly increased compared to sham mice. However, treatment with iExo attenuated these changes, significantly improving renal function and tissue damage, similar to the renoprotective effects of iMSCs on I/R injury. Significant induction of activated ERK 1/2 signaling molecules was observed in mice treated with iExo compared to those in the I/R injury group.
The present study demonstrates that iExo administration ameliorated renal damage following I/R, suggesting that iMSC-derived exosomes may provide a novel therapeutic approach for AKI treatment.
背景/目的：肾缺血再灌注（I/R）是急性肾损伤（AKI）的主要原因，与高发病率和死亡率密切相关。研究表明，诱导多能干细胞（iPSC）来源的间充质干细胞（iMSC）在肾缺血中发挥强大的治疗作用。然而，iMSC来源的外泌体（iExo）对I/R损伤的疗效仍 largely 未知。
使用改良的一步法将人iPSC分化为iMSC。采用超滤结合纯化的方法从iMSC中分离iExo。在小鼠模型的I/R损伤后给予iExo。通过肾功能、组织学变化以及氧化应激、炎症和凋亡标志物的表达来评估iExo对I/R损伤的影响。此外，我们评估了其与细胞外信号调节激酶（ERK）1/2信号通路的关联。
遭受I/R损伤的小鼠表现出典型的AKI模式；与假手术小鼠相比血清肌酐水平、肾小管坏死、凋亡、炎性细胞因子产生和氧化应激显著增加。然而，iExo治疗减轻了这些变化，显著改善了肾功能和组织损伤，类似于iMSC对I/R损伤的肾保护作用。与I/R损伤组相比，在接受iExo治疗的小鼠中观察到活化的ERK 1/2信号分子的显著诱导。
本研究表明给予iExo可改善I/R后的肾损伤，提示iMSC来源的外泌体可能为AKI治疗提供一种新的治疗方法。
