骨髓来源的内皮祖细胞和肝干细胞移植可改善肝纤维化大鼠的肝纤维化。
Transplantation of bone marrow-derived endothelial progenitor cells and hepatocyte stem cells from liver fibrosis rats ameliorates liver fibrosis.
机构信息
Department of Gastroenterology and Hepatology, the People's Hospital of Zhengzhou University (the Henan Provincial People's Hospital), Zhengzhou 450003, Henan Province, China.
Department of Oncology, Henan Provincial Rongjun Hospital, Xinxiang 453000, Henan Province, China.
出版信息
World J Gastroenterol. 2018 Jan 14;24(2):237-247. doi: 10.3748/wjg.v24.i2.237.
AIM
To explore the effectiveness for treating liver fibrosis by combined transplantation of bone marrow-derived endothelial progenitor cells (BM-EPCs) and bone marrow-derived hepatocyte stem cells (BDHSCs) from the liver fibrosis environment.
METHODS
The liver fibrosis rat models were induced with carbon tetrachloride injections for 6 wk. BM-EPCs from rats with liver fibrosis were obtained by different rates of adherence and culture induction. BDHSCs from rats with liver fibrosis were isolated by magnetic bead cell sorting. Tracing analysis was conducted by labeling EPCs with PKH26 to show EPC location in the liver. Finally, BM-EPCs and/or BDHSCs transplantation into rats with liver fibrosis were performed to evaluate the effectiveness of BM-EPCs and/or BDHSCs on liver fibrosis.
RESULTS
Normal functional BM-EPCs from liver fibrosis rats were successfully obtained. The co-expression level of CD133 and VEGFR2 was 63.9% ± 2.15%. Transplanted BM-EPCs were located primarily in/near hepatic sinusoids. The combined transplantation of BM-EPCs and BDHSCs promoted hepatic neovascularization, liver regeneration and liver function, and decreased collagen formation and liver fibrosis degree. The VEGF levels were increased in the BM-EPCs (707.10 ± 54.32) and BM-EPCs/BDHSCs group (615.42 ± 42.96), compared with those in the model group and BDHSCs group ( < 0.05). Combination of BM-EPCs/BDHSCs transplantation induced maximal up-regulation of PCNA protein and HGF mRNA levels. The levels of alanine aminotransferase (AST), aspartate aminotransferase, total bilirubin (TBIL), prothrombin time (PT) and activated partial thromboplastin time in the BM-EPCs/BDHSCs group were significantly improved, to be equivalent to normal levels ( > 0.05) compared with those in the BDHSC (AST, TBIL and PT, < 0.05) and BM-EPCs (TBIL and PT, < 0.05) groups. Transplantation of BM-EPCs/BDHSCs combination significantly reduced the degree of liver fibrosis (staging score of 1.75 ± 0.25 BDHSCs 2.88 ± 0.23 or BM-EPCs 2.75 ± 0.16, < 0.05).
CONCLUSION
The combined transplantation exhibited maximal therapeutic effect compared to that of transplantation of BM-EPCs or BDHSCs alone. Combined transplantation of autogenous BM-EPCs and BDHSCs may represent a promising strategy for the treatment of liver fibrosis, which would eventually prevent cirrhosis and liver cancer.
目的
探讨骨髓源内皮祖细胞（BM-EPCs）和骨髓源肝干细胞（BDHSCs）联合移植治疗肝纤维化的疗效。
方法
采用四氯化碳注射 6 周诱导肝纤维化大鼠模型。通过不同的贴壁率和培养诱导获得肝纤维化大鼠的 BM-EPCs。采用磁珠细胞分选分离肝纤维化大鼠的 BDHSCs。通过用 PKH26 标记 EPCs 进行示踪分析，以显示 EPC 在肝脏中的位置。最后，将 BM-EPCs 和/或 BDHSCs 移植到肝纤维化大鼠中，以评估 BM-EPCs 和/或 BDHSCs 对肝纤维化的疗效。
结果
成功获得了来自肝纤维化大鼠的正常功能 BM-EPCs。CD133 和 VEGFR2 的共表达水平为 63.9%±2.15%。移植的 BM-EPCs 主要位于/靠近肝窦。BM-EPCs 和/或 BDHSCs 的联合移植促进了肝内新生血管形成、肝再生和肝功能，并减少了胶原形成和肝纤维化程度。与模型组和 BDHSCs 组相比，BM-EPCs（707.10±54.32）和 BM-EPCs/BDHSCs 组（615.42±42.96）中的 VEGF 水平升高（<0.05）。BM-EPCs/BDHSCs 联合移植诱导 PCNA 蛋白和 HGF mRNA 水平最大程度上调。与 BDHSCs（AST、TBIL 和 PT，<0.05）和 BM-EPCs（TBIL 和 PT，<0.05）组相比，BM-EPCs/BDHSCs 组的丙氨酸氨基转移酶（AST）、天冬氨酸氨基转移酶、总胆红素（TBIL）、凝血酶原时间（PT）和部分凝血活酶时间明显改善，接近正常水平（>0.05）。BM-EPCs/BDHSCs 联合移植显著降低了肝纤维化程度（分期评分：BDHSCs 2.88±0.23 或 BM-EPCs 2.75±0.16，<0.05）。
结论
与单独移植 BM-EPCs 或 BDHSCs 相比，联合移植显示出最大的治疗效果。自体 BM-EPCs 和 BDHSCs 的联合移植可能是治疗肝纤维化的一种很有前途的策略，最终可以预防肝硬化和肝癌。
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