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脂肪间充质干细胞移植治疗大鼠肝损伤的作用及其相关信号通路

Therapeutic potential and related signal pathway of adipose-derived stem cell transplantation for rat liver injury.

机构信息

Department of Hepatobiliary and Pancreatic Surgery, Key Laboratory of Multi-Organ Transplantation of Ministry of Public Health, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.

出版信息

Hepatol Res. 2009 Aug;39(8):822-32. doi: 10.1111/j.1872-034X.2009.00506.x. Epub 2009 Mar 25.

Abstract

AIM

Liver transplantation is the only currently effective therapy for end-stage chronic liver disease and severe acute liver failure, but its use is limited by high cost and a shortage of allografts. Here we explored the effectiveness of transplanting adipose-derived stem cells (ADSCs) into rats with experimentally induced liver injury.

METHODS

ADSCs obtained from rats were hepatogenic induced in vitro with MAPK pathways inhibitors preconditioning. In vivo, ADSCs were transplanted into rats via different routes and serum liver function markers from post-operative rats were tested.

RESULTS

When grown in adipogenic induction medium, ADSCs were able to differentiate into adipocytes. In hepatogenic induction medium, ADSCs were able to differentiate into hepatocyte-like cells, with appropriate changes in morphology and appropriately elevated expression of hepatocyte-specific markers. ERK1/2 phosphorylation activity was also significantly upregulated during the hepatogenic differentiation process, and was blocked by the ERK/MAPK pathway-specific inhibitor PD98059. In a rat liver injury model, intravenously injected ADSCs successfully engrafted into recipient livers. We found that injection via the hepatic portal vein was more efficient than via the dorsal vein of the penis. ADSC transplantation into damaged livers significantly decreased the level of serum liver enzymes such as alanine aminotransferase and aspartate aminotransferase, and improved serum albumin level. Both the number of engrafted cells and the improvement of liver function reached a peak two weeks after transplantation.

CONCLUSION

Transplanted ADSCs appear to be therapeutically effective in the rat liver injury model, which may ultimately provide a therapeutic alternative to liver transplantation in human patients.

摘要

目的

肝移植是治疗终末期慢性肝病和严重急性肝衰竭的唯一有效方法,但由于费用高和供体短缺,其应用受到限制。本研究旨在探讨将脂肪来源干细胞(ADSCs)移植到实验性肝损伤大鼠体内的有效性。

方法

从大鼠中分离得到 ADSC,用 MAPK 通路抑制剂预处理进行体外肝向诱导。体内实验中,通过不同途径将 ADSC 移植到大鼠体内,并检测术后大鼠血清肝功能标志物。

结果

当在成脂诱导培养基中培养时,ADSC 能够分化为脂肪细胞。在成肝细胞诱导培养基中,ADSC 能够分化为肝细胞样细胞,形态适当改变,肝细胞特异性标志物表达水平适当升高。在肝向分化过程中,ERK1/2 磷酸化活性也显著上调,并被 ERK/MAPK 通路特异性抑制剂 PD98059 阻断。在大鼠肝损伤模型中,静脉注射的 ADSC 成功植入受体肝脏。我们发现经肝门静脉注射比经阴茎背静脉注射更有效。ADSC 移植到受损肝脏中可显著降低血清转氨酶(如丙氨酸氨基转移酶和天冬氨酸氨基转移酶)和白蛋白水平。移植后两周,植入细胞数量和肝功能改善均达到峰值。

结论

移植的 ADSC 在大鼠肝损伤模型中具有治疗效果,这可能为人类患者的肝移植治疗提供一种替代方法。

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