Protective Effects of Human Liver Stem Cell-Derived Extracellular Vesicles in a Mouse Model of Hepatic Ischemia-Reperfusion Injury

被引:16
作者
Calleri, Alberto [1 ]
Roggio, Dorotea [1 ]
Navarro-Tableros, Victor [2 ]
De Stefano, Nicola [1 ]
Pasquino, Chiara [3 ]
David, Ezio [4 ]
Frigatti, Giada [1 ]
Rigo, Federica [1 ,5 ]
Antico, Federica [5 ]
Caropreso, Paola [6 ]
Patrono, Damiano [1 ]
Bruno, Stefania [3 ]
Romagnoli, Renato [1 ]
机构
[1] Univ Turin, AOU Citta Salute & Sci Torino, Liver Transplantat Ctr, Gen Surg 2U, Turin, Italy
[2] Univ Torino, 2i3T Soc Gest Incubatore Imprese & Trasferimento, Scarl Mol Biotechnol Ctr MBC, Turin, Italy
[3] Univ Turin, Dept Med Sci, Turin, Italy
[4] AOU Citta Salute & Sci Torino, Pathol Unit, Molinette Hosp, Turin, Italy
[5] ONLUS Mol Biotechnol Ctr MBC, Forb Fdn Ric Biomed, Turin, Italy
[6] AOU Citta Salute & Sci Torino, Molinette Hosp, Clin Biochem Lab, Turin, Italy
关键词
Ischemia-reperfusion; Hepatic inflammation; Adult stem cells; Microvesicles; Liver regeneration; ISCHEMIA/REPERFUSION INJURY; KUPFFER CELLS; MECHANISMS; EXOSOMES; MICROVESICLES; INSIGHTS; NECROSIS;
D O I
10.1007/s12015-020-10078-7
中图分类号
Q813 [细胞工程];
学科分类号
摘要
Hepatic ischemia-reperfusion injury (IRI) is observed in liver transplantation and hepato-biliary surgery and is associated with an inflammatory response. Human liver stem cell-derived extracellular vesicles (HLSC-EV) have been demonstrated to reduce liver damage in different experimental settings by accelerating regeneration and by modulating inflammation. The aim of the present study was to investigate whether HLSC-EV may protect liver from IRI in a mouse experimental model. Segmental IRI was obtained by selective clamping of intrahepatic pedicles for 90 min followed by 6 h of reperfusion. HLSC-EV were administered intravenously at the end of the ischemic period and histopathological and biochemical alterations were evaluated in comparison with controls injected with vehicle alone. Intra liver localization of labeled HLSC-EV was assessed by in in vivo Imaging System (IVIS) and the internalization into hepatocytes was confirmed by fluorescence analyses. As compared to the control group, administration of 3 x 10(9) particles (EV1 group) significantly reduced alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) release, necrosis extension and cytokines expression (TNF-alpha, CCL-2 and CXCL-10). However, the administration of an increased dose of HLSC-EV (7.5 x 10(9) particles, EV2 group) showed no significant improvement in respect to controls at enzyme and histology levels, despite a significantly lower cytokine expression. In conclusion, this study demonstrated that 3 x 10(9) HLSC-EV were able to modulate hepatic IRI by preserving tissue integrity and by reducing transaminases release and inflammatory cytokines expression. By contrast, a higher dose was ineffective suggesting a restricted window of biological activity.
引用
收藏
页码:459 / 470
页数:12
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