Hepatoprotective effect of exosomes from human-induced pluripotent stem cell-derived mesenchymal stromal cells against hepatic ischemia-reperfusion injury in rats

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• 作者：Kate Nong¹ ; ^&dagger ; ; Weiwei Wang² ; ^&dagger ; ; Xin Niu³ ; Bin Hu³ ; Chenchao Ma¹ ; Yueqing Bai⁴ ; Bo Wu¹ ; Yang Wang³ ; ^{wangy63cn@126.com" class="auth_mail" title="E-mail the corresponding author} ; Kaixing Ai¹ ; ⁵ ; ^{akxing8258@126.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：apoptosis ; exosomes ; hepatic ischemia-reperfusion injury ; induced pluripotent stem cells ; mesenchymal stromal cells
• 刊名：Cytotherapy
• 出版年：2016
• 出版时间：December 2016
• 年：2016
• 卷：18
• 期：12
• 页码：1548-1559
• 全文大小：5781 K

文摘

This study aimed to evaluate the effect of exosomes produced by human-induced pluripotent stem cell–derived mesenchymal stromal cells (hiPSC-MSCs-Exo) on hepatic ischemia-reperfusion (I/R) injury.

Methods

Exosomes were isolated and concentrated from conditioned medium using ultracentrifugation and ultrafiltration. hiPSC-MSCs-Exo were injected systemically via the inferior vena cava in a rat model of 70% warm hepatic I/R injury, and the therapeutic effect was evaluated. The serum levels of transaminases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) were measured using an automatic analyzer. The expression of inflammatory factors was measured using enzyme-linked immunosorbent assay (ELISA). Histological changes indicated changes in pathology and inflammatory infiltration in liver tissue. Apoptosis of hepatic cells in liver tissue was measured using terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) staining along with apoptotic markers.

Results

hiPSCs were efficiently induced into hiPSC-MSCs with typical MSC characteristics. hiPSC-MSCs-Exo had diameters ranging from 50 to 60 nm and expressed exosomal markers (CD9, CD63 and CD81). Hepatocyte necrosis and sinusoidal congestion were markedly suppressed with a lower Suzuki score after hiPSC-MSCs-Exo administration. The levels of the hepatocyte injury markers AST and ALT were significantly lower in the treated group than in the control group. Inflammatory markers, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6 and high mobility group box 1 (HMGB1), were significantly reduced after administration of hiPSC-MSCs-Exo, which suggests that the exosomes have a role in suppressing the inflammatory response. Additionally, in liver tissues from the experimental group, the levels of apoptotic markers, such as caspase-3 and bax, were significantly lower and the levels of oxidative markers, such as glutathione (GSH), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD), were significantly higher than in the control group. These data point to an anti-apoptotic, anti-oxidative stress response role for hiPSC-MSCs-Exo.

Conclusions

Our results demonstrated that hiPSC-MSCs-Exo alleviate hepatic I/R injury, possibly via suppression of inflammatory responses, attenuation of the oxidative stress response and inhibition of apoptosis.