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血红素加氧酶-1 修饰的骨髓间充质干细胞联合常温机械灌注保护脑死亡供肝。

Heme oxygenase-1-modified bone marrow mesenchymal stem cells combined with normothermic machine perfusion to protect donation after circulatory death liver grafts.

机构信息

Tianjin First Central Hospital Clinic Institute, Tianjin Medical University, Tianjin, 300070, People's Republic of China.

Department of Organ Transplantation, Tianjin First Central Hospital, No. 24 Fukang Road, Nankai District, Tianjin, 300192, People's Republic of China.

出版信息

Stem Cell Res Ther. 2020 Jun 5;11(1):218. doi: 10.1186/s13287-020-01736-1.

DOI:10.1186/s13287-020-01736-1
PMID:32503631
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7275432/
Abstract

BACKGROUND

Donation after circulatory death (DCD) liver grafts have a poor prognosis after transplantation. We investigated whether the outcome of DCD donor organs can be improved by heme oxygenase 1 (HO-1)-modified bone marrow-derived mesenchymal stem cells (BMMSCs) combined with normothermic machine perfusion (NMP), and explored its underlying mechanisms.

METHODS

BMMSCs were isolated, cultured, and transduced with the HO-1 gene. An NMP system was established. DCD rat livers were obtained, preserved by different methods, and the recipients were divided into 5 groups: sham operation, static cold storage (SCS), NMP, BMMSCs combined with NMP, and HO-1/BMMSCs combined with NMP (HBP) groups. Rats were sacrificed at 1, 7, and 14 days after surgery; their blood and liver tissue samples were collected; and liver enzyme and cytokine levels, liver histology, high-mobility group box 1 (HMGB1) levels in monocytes and liver tissues, and expression of Toll-like receptor 4 (TLR4) pathway-related molecules were evaluated.

RESULTS

After liver transplantation, the SCS group showed significantly increased transaminase levels, liver tissue damage, and shorter survival time. The HBP group showed lower transaminase levels, intact liver morphology, prolonged survival time, and decreased serum and liver proinflammatory cytokine levels. In the NMP and SCS groups, HMGB1 expression in the serum, monocytes, and liver tissues and TLR4 pathway-related molecule expression were significantly decreased.

CONCLUSIONS

HO-1/BMMSCs combined with NMP exerted protective effects on DCD donor liver and significantly improved recipient prognosis. The effect of HO-1/BMMSCs was greater than that of BMMSCs and was mediated via HMGB1 expression and TLR4 pathway inhibition.

摘要

背景

心跳停止后捐献(DCD)的肝脏移植物在移植后预后不良。我们研究了血红素加氧酶 1(HO-1)修饰的骨髓间充质干细胞(BMMSCs)联合体温非循环机器灌注(NMP)是否可以改善 DCD 供体器官的结果,并探讨了其潜在机制。

方法

分离、培养 BMMSCs 并转导 HO-1 基因。建立 NMP 系统。获取 DCD 大鼠肝脏,采用不同方法保存,并将受体分为 5 组:假手术组、静态冷保存(SCS)组、NMP 组、BMMSCs 联合 NMP 组和 HO-1/BMMSCs 联合 NMP 组(HBP 组)。术后 1、7 和 14 天处死大鼠,采集血液和肝组织样本;评估肝酶和细胞因子水平、肝组织学、单核细胞和肝组织中高迁移率族蛋白 1(HMGB1)水平以及 Toll 样受体 4(TLR4)通路相关分子的表达。

结果

肝移植后,SCS 组转氨酶水平明显升高,肝组织损伤,存活时间缩短。HBP 组转氨酶水平较低,肝形态完整,存活时间延长,血清和肝前炎症细胞因子水平降低。在 NMP 和 SCS 组中,血清、单核细胞和肝组织中 HMGB1 表达及 TLR4 通路相关分子表达明显降低。

结论

HO-1/BMMSCs 联合 NMP 对 DCD 供体肝具有保护作用,并显著改善受体预后。HO-1/BMMSCs 的作用大于 BMMSCs,是通过 HMGB1 表达和 TLR4 通路抑制介导的。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd78/7275432/a7fd321f0282/13287_2020_1736_Fig9_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd78/7275432/3c92632e4996/13287_2020_1736_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd78/7275432/f263392c1ccb/13287_2020_1736_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd78/7275432/9a1bb9e39933/13287_2020_1736_Fig7_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd78/7275432/a7fd321f0282/13287_2020_1736_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd78/7275432/ba8e941d595e/13287_2020_1736_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd78/7275432/398707ab0f34/13287_2020_1736_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd78/7275432/af983cb5a15b/13287_2020_1736_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd78/7275432/3c92632e4996/13287_2020_1736_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd78/7275432/f263392c1ccb/13287_2020_1736_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd78/7275432/9a1bb9e39933/13287_2020_1736_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd78/7275432/67be80bd2c08/13287_2020_1736_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd78/7275432/a7fd321f0282/13287_2020_1736_Fig9_HTML.jpg

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