College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China.
College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China.
Biomed Pharmacother. 2023 Dec 31;169:115873. doi: 10.1016/j.biopha.2023.115873. Epub 2023 Nov 16.
Hepatic ischemia-reperfusion injury (HIRI) is a complication of hepatectomy that affects the functional recovery of the remnant liver, which has been demonstrated to be associated with pyroptosis and apoptosis. Mesenchymal stem cells (MSCs) can protect against HIRI in rodents. Paracrine mechanisms of MSCs indicated that MSCs-derived exosomes (MSCs-exo) are one of the important components within the paracrine substances of MSCs. Moreover, miniature pigs are ideal experimental animals in comparative medicine compared to rodents. Accordingly, this study aimed to investigate whether hepatectomy combined with HIRI in miniature pigs would induce pyroptosis and whether adipose-derived MSCs (ADSCs) and their exosomes (ADSCs-exo) could positively mitigate apoptosis and pyroptosis. The study also compared the differences in the effects and the role of ADSCs and ADSCs-exo in pyroptosis and apoptosis. Results showed that severe ultrastructure damage occurred in liver tissues and systemic inflammatory response was induced after surgery, with TLR4/MyD88/NFκB/HMGB1 activation, NLRP3-ASC-Caspase1 complex generation, GSDMD revitalization, and IL-1β, IL-18, and LDH elevation in the serum. Furthermore, expression of Fas-Fasl-Caspase8 and CytC-APAF1-Caspase9 was increased in the liver. The ADSCs or ADSCs-exo intervention could inhibit the expression of these indicators and improve the ultrastructural pathological changes and systemic inflammatory response. There was no significant difference between the two intervention groups. In summary, ADSCs-exo could effectively inhibit pyroptosis and apoptosis similar to ADSCs and may be considered a safe and effective cell-free therapy to protect against liver injury.
肝缺血再灌注损伤（HIRI）是肝切除术后的一种并发症，影响残余肝脏的功能恢复，已证明与细胞焦亡和细胞凋亡有关。间充质干细胞（MSCs）可在啮齿动物中保护 HIRI。MSCs 的旁分泌机制表明，MSCs 衍生的外泌体（MSCs-exo）是 MSCs 旁分泌物质的重要组成部分之一。此外，与啮齿动物相比，小型猪是比较医学中的理想实验动物。因此，本研究旨在探讨小型猪肝切除联合 HIRI 是否会诱导细胞焦亡，以及脂肪来源的 MSCs（ADSCs）及其外泌体（ADSCs-exo）是否能积极减轻凋亡和细胞焦亡。本研究还比较了 ADSCs 和 ADSCs-exo 在细胞焦亡和凋亡中的作用和差异。结果表明，手术后肝脏组织出现严重的超微结构损伤，并诱导全身炎症反应，TLR4/MyD88/NFκB/HMGB1 激活，NLRP3-ASC-Caspase1 复合物生成，GSDMD 复活，以及血清中 IL-1β、IL-18 和 LDH 升高。此外，肝脏中 Fas-Fasl-Caspase8 和 CytC-APAF1-Caspase9 的表达增加。ADSCs 或 ADSCs-exo 的干预可以抑制这些指标的表达，改善超微结构的病理变化和全身炎症反应。两种干预组之间没有显著差异。总之，ADSCs-exo 可以有效地抑制细胞焦亡和凋亡，与 ADSCs 相似，可作为一种安全有效的无细胞治疗方法，用于保护肝脏免受损伤。
