The adipose-derived mesenchymal stem cell secretome promotes hepatic regeneration in miniature pigs after liver ischaemia-reperfusion combined with partial resection.
The adipose-derived mesenchymal stem cell secretome promotes hepatic regeneration in miniature pigs after liver ischaemia-reperfusion combined with partial resection.
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脂肪间充质干细胞分泌组促进小型猪肝脏缺血再灌注联合部分切除后的肝再生
DOI：
10.1186/s13287-021-02284-y
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发表时间：
2021-03-30
影响因子：
7.5
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Jiao Z;Ma Y;Zhang Q;Wang Y;Liu T;Liu X;Piao C;Liu B;Wang H
肝脏缺血再灌注损伤(HIRI)在复杂的肝脏手术中是不可避免的，是导致术后并发症和肝功能障碍的主要因素。研究表明，干细胞的旁分泌机制可能是移植后组织修复和功能改善所必需的。然而，脂肪来源的间充质干细胞分泌体(ASC-分泌体)在大动物肝脏再生中的作用尚不清楚。方法24只小型猪在腹腔镜下肝脏缺血再灌注联合肝部分切除后，随机分为生理盐水组、DMEM组、ASC组和ASC-分泌组。分别于术前、术后1、3、7 取材，观察肝组织病理学、血清炎症反应、肝功能、血管生成相关因子及肝组织再生相关基因和蛋白的变化。结果肝缺血再灌注联合肝部分切除后(1、3 d：P<； 0.0 1)，ASCs和ASC分泌体改变了肝组织的病理损伤。与生理盐水对照组和DMEM对照组相比，ASC-分泌组ALP(1和3 d：P<； 0.0 5)、ALT(1 d：P<； 0.0 1；3 d：P<； 0.0 5)和AST(1和3 d：P<； 0.0 1)的表达水平显著降低，从而促进了肝功能的恢复。此外，检测血清中肿瘤坏死因子-α和IL-1β(1 天：P<； 0.0 1；3 d：P<； 0.0 5)、IL-6(1和3 d：P<； 0.0 5)和IL-10(1和3 d：P<； 0.0 1)的表达水平，证实ASC分泌体具有明显的抗炎作用。此外，ASC分泌体增加血管生成素-1(3 d：P<； 0.0 1)、血管紧张素-2(3和7 d：P<； 0.0 1)和血管内皮生长因子(1和7 d：P<； 0.0 5；3 d：P<； 0.0 1)的表达，促进肝再生过程中的血管生成。促进肝细胞生长因子和细胞周期蛋白D1mRNA的表达(1和3 d：P<； 0.01)，上调p-STAT3(1和3 d：P<； 0.01)、增殖细胞核抗原和Ki67的表达(1和3 d：P<； 0.01；7 d：P<； 0.05)，抑制SOCS3的负反馈(1和3 d：P<； 0.01)，降低β的基因表达(3 d：P<；P<； )。细胞因子和生长因子包括肿瘤坏死因子α、白介素6、白介素1β、血管紧张素转换酶1、血管紧张素转换酶2、血管内皮生长因子和b-FGF。结论肝细胞分泌体能减轻缺血再灌注联合肝部分切除所致的炎症反应，促进肝再生。
BackgroundHepatic ischaemia-reperfusion injury (HIRI) is inevitable in complicated liver surgery and is a major factor leading to postoperative complications and liver dysfunction. Studies have shown that the paracrine mechanisms of stem cell may be essential to tissue repair and functional improvement after transplantation. However, the role of the adipose-derived mesenchymal stem cell secretome (ASC-secretome) in liver regeneration in large animals remains to be determined.MethodsTwenty-four miniature pigs were subjected to laparoscopic liver ischaemia-reperfusion combined with partial hepatectomy and divided into the following four groups: the saline group, the DMEM group, the ASC group and the ASC-secretome group. Serum and liver tissue samples were collected before the operation and at 1, 3 and 7 days after the operation, and changes in tissue pathology, serum inflammation, liver function, angiogenesis-related factors and liver tissue regeneration-related genes and proteins were evaluated.ResultsDetailed histological analysis showed that ASCs and the ASC-secretome changed pathological damage to liver tissue after liver ischaemia-reperfusion combined with partial hepatectomy (1 and 3 days:p< 0.01). Compared with the saline and DMEM control groups, the ASC-secretome group had significantly reduced expression levels of ALP (1 and 3 days:p< 0.05), ALT (1 day:p< 0.01; 3 days:p< 0.05) and AST (1 and 3 days:p< 0.01), which promoted the recovery of liver function. Moreover, detection of the expression levels of TNF-α and IL-1β (1 day:p< 0.01; 3 days:p< 0.05), IL-6 (1 and 3 days:p< 0.05) and IL-10 (1 and 3 days:p< 0.01) in serum confirmed that the ASC-secretome had obvious anti-inflammatory effects. In addition, the ASC-secretome increased the expression levels of ANG-1 (3 days:p< 0.01), ANG-2 (3 and 7 days:p< 0.01) and VEGF (1 and 7 days:p< 0.05; 3 days:p< 0.01) and promoted angiogenesis during liver regeneration. Moreover, it promoted the mRNA expression of HGF and Cyclin D1 (1 and 3 days:p< 0.01); increased the levels of p-STAT3 (1 and 3 days:p< 0.01), PCNA and Ki67 (1 and 3 days:p< 0.01; 7 days:p< 0.05); inhibited the negative feedback of SOCS3 (1 and 3 days:p< 0.01); and decreased the mRNA expression of TGF-β (3 days:p< 0.01). The cytokines and growth factors detected in the ASC-secretome included TNF-α, IL-6, IL-1β, ANG-1, ANG-2, VEGF and b-FGF.ConclusionThe ASC-secretome alleviates the inflammatory response induced by ischaemia-reperfusion combined with partial hepatectomy in miniature pigs and promotes liver regeneration.
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