同种异体骨髓基质细胞肝内移植治疗急性肝损伤疗效观察的实验研究
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摘要
背景及目的:近期研究已经显示骨髓基质细胞在活体内、外能够诱导分化为肝细胞,骨髓基质细胞移植能够减轻受损肝脏的炎症反应、胶原沉积以及肝脏重塑进而修复受损肝脏。上述研究提示同种骨髓基质细胞移植有望治疗肝脏疾病。具有多向分化潜能的骨髓基质细胞尽管能够分化为肝细胞,但对骨髓基质细胞移植到受损肝脏的活体内的治疗效用的评估报道却较少。本研究的目的是观察骨髓基质细胞肝内移植治疗D-氨基半乳糖诱导的兔急性肝损伤的疗效。
方法:骨髓基质细胞由雄性白兔的股骨和胫骨的骨髓中提取,分离、培养及传代3周并观察其形态学特征,用D-氨基半乳糖诱导建立兔急性肝损伤模型,模型兔(n=58)随机分为2组:实验组(n=24):直接肝脏内注射5 ml骨髓基质细胞(约2×10~7个);对照组(n=34):直接肝脏内注射5 ml D-hanks液。每天观察各组实验兔的行为变化、生存率、肝功能(ALT,AST,ALB和TBIL)的改变;骨髓基质细胞移植后1、2、4周分别处死两组实验兔,每次7只,观察肝脏组织病理学变化及肝脏坏死程度。所有数据资料均借助SPSS 13.0统计分析。
结果:实验组1周后的生存率高于对照组(95.8%vs 70.6%,P＜0.05),而2周后的生存率较对照组未见显著性改善(100%vs 82.4%,P＞0.05)。肝功能的检测显示:与对照组比较,实验组在细胞移植后血清白蛋白明显升高(p＜0.05),转氨酶ALT和AST均有显著性降低(p＜0.05),但两组动物的TBIL水平的变化并无统计学意义(p＞0.05)。组织病理学评分的结果显示:与对照组比较,骨髓基质细胞移植到受损肝脏后可显著减轻肝脏坏死程度及刺激肝细胞再生进而发挥强大地抗坏死作用(p＜0.001)。
结论:骨髓基质细胞肝内移植可有效修复D-氨基半乳糖诱导的兔严重急性肝损伤。骨髓基质细胞直接肝内注射移植为实验动物模型简单的移植方式。
BACKGROUND/AIMS Recent reports have shown the capacity of bone marrow stromal cells(BMSCs)to differentiate into hepatocytes in vitro and in vivo.BMSCs administration could repair injured liver through reducing inflammation,collagen deposition,and remodeling. These results provide a clue that the syngenic transplantation of BMSCs is a promising treatment for liver disease.Pluripotent BMSCs can differentiate into hepatocytes,but few reports address the therapeutic effect of transplanting these stem cells into damaged liver in vivo.The aim of this study was to investigate the therapeutic effect of infusion of BMSCs on acute hepatic injury(AHI)rabbits induced by D-galactosamine.
METHODS BMSCs were derived from bone marrow obtained from femoral and tibial bones of male albino rabbits.BMSCs were separated,grown,and propagated in culture for 3 weeks and were characterized morphologically.They were then infused directly into livers of syngenic male rabbits that received D-galactosamine injection to induce liver injury.AHI rabbits(n=58)were divided into 2 random groups on the 24th hour of D-GalN:D-GalN/BMSCs(n=24),to infuse 5 ml(about 2×10~7)BMSCs directly as treated group.D-GalN/D-hanks(n =34),to infuse the same dose of D-hanks as control.Then behavioral changes:of rabbits were monitored everyday.The survival rates were observed and liver functions(ALT,AST,ALB and TBIL)were estimated for all groups.After 1-4 wk of BMSCs administration,all rabbits were killed with different time(1 wk,2 wk,4 wk)respectively and histopathological changes and degrees of necrosis in the hepatic tissues were assessed also.Two histopathologists blinded to treated group and each other's results measured liver histopathological scores.All data should be analyzed by SPSS 13.0.
RESULTS Survival rate of D-GalN/BMSCs Group 1 weeks later was higher than that of control(95.8%vs 70.6%,P＜0.05).On the other hand,the survival rate of D-GalN/BMSCs Group 2 weeks later was not improved significantly as compared with that of control(100%vs 82.4%,P＞0.05).With regard to liver function,there was also a significant improvement and elevation of Serum albumin in the D-GalN/BMSCs group compared to the D-GalN/D-hanks group (p＜0.05).As regard to the liver enzyme ALT and AST,there was also a significant decrease of its level in the D-GalN/BMSCs group compared to the D-GalN/D-hanks group(p＜0.05).However,the level of TBIL of 2 groups was statistically nonsignificant(p＞0.05).Results of the histopathological scores showed that BMSCs have a significant anti-injurious activities as evidenced by the significant decrease in liver necrosis as well as the stimulate hepatocytes proliferation in the D-GalN/BMSCs group compared to the D-GalN/D-hanks group(p＜0.001).
CONCLUSIONS The transplantation of BMSCs effectively contribute to the repair of the severely acute liver injury in D-GalN-induced rabbits.Injection of BMSCs directly into the liver is the simple route of administration in experimental model.
方法:骨髓基质细胞由雄性白兔的股骨和胫骨的骨髓中提取,分离、培养及传代3周并观察其形态学特征,用D-氨基半乳糖诱导建立兔急性肝损伤模型,模型兔(n=58)随机分为2组:实验组(n=24):直接肝脏内注射5 ml骨髓基质细胞(约2×10~7个);对照组(n=34):直接肝脏内注射5 ml D-hanks液。每天观察各组实验兔的行为变化、生存率、肝功能(ALT,AST,ALB和TBIL)的改变;骨髓基质细胞移植后1、2、4周分别处死两组实验兔,每次7只,观察肝脏组织病理学变化及肝脏坏死程度。所有数据资料均借助SPSS 13.0统计分析。
结果:实验组1周后的生存率高于对照组(95.8%vs 70.6%,P＜0.05),而2周后的生存率较对照组未见显著性改善(100%vs 82.4%,P＞0.05)。肝功能的检测显示:与对照组比较,实验组在细胞移植后血清白蛋白明显升高(p＜0.05),转氨酶ALT和AST均有显著性降低(p＜0.05),但两组动物的TBIL水平的变化并无统计学意义(p＞0.05)。组织病理学评分的结果显示:与对照组比较,骨髓基质细胞移植到受损肝脏后可显著减轻肝脏坏死程度及刺激肝细胞再生进而发挥强大地抗坏死作用(p＜0.001)。
结论:骨髓基质细胞肝内移植可有效修复D-氨基半乳糖诱导的兔严重急性肝损伤。骨髓基质细胞直接肝内注射移植为实验动物模型简单的移植方式。
BACKGROUND/AIMS Recent reports have shown the capacity of bone marrow stromal cells(BMSCs)to differentiate into hepatocytes in vitro and in vivo.BMSCs administration could repair injured liver through reducing inflammation,collagen deposition,and remodeling. These results provide a clue that the syngenic transplantation of BMSCs is a promising treatment for liver disease.Pluripotent BMSCs can differentiate into hepatocytes,but few reports address the therapeutic effect of transplanting these stem cells into damaged liver in vivo.The aim of this study was to investigate the therapeutic effect of infusion of BMSCs on acute hepatic injury(AHI)rabbits induced by D-galactosamine.
METHODS BMSCs were derived from bone marrow obtained from femoral and tibial bones of male albino rabbits.BMSCs were separated,grown,and propagated in culture for 3 weeks and were characterized morphologically.They were then infused directly into livers of syngenic male rabbits that received D-galactosamine injection to induce liver injury.AHI rabbits(n=58)were divided into 2 random groups on the 24th hour of D-GalN:D-GalN/BMSCs(n=24),to infuse 5 ml(about 2×10~7)BMSCs directly as treated group.D-GalN/D-hanks(n =34),to infuse the same dose of D-hanks as control.Then behavioral changes:of rabbits were monitored everyday.The survival rates were observed and liver functions(ALT,AST,ALB and TBIL)were estimated for all groups.After 1-4 wk of BMSCs administration,all rabbits were killed with different time(1 wk,2 wk,4 wk)respectively and histopathological changes and degrees of necrosis in the hepatic tissues were assessed also.Two histopathologists blinded to treated group and each other's results measured liver histopathological scores.All data should be analyzed by SPSS 13.0.
RESULTS Survival rate of D-GalN/BMSCs Group 1 weeks later was higher than that of control(95.8%vs 70.6%,P＜0.05).On the other hand,the survival rate of D-GalN/BMSCs Group 2 weeks later was not improved significantly as compared with that of control(100%vs 82.4%,P＞0.05).With regard to liver function,there was also a significant improvement and elevation of Serum albumin in the D-GalN/BMSCs group compared to the D-GalN/D-hanks group (p＜0.05).As regard to the liver enzyme ALT and AST,there was also a significant decrease of its level in the D-GalN/BMSCs group compared to the D-GalN/D-hanks group(p＜0.05).However,the level of TBIL of 2 groups was statistically nonsignificant(p＞0.05).Results of the histopathological scores showed that BMSCs have a significant anti-injurious activities as evidenced by the significant decrease in liver necrosis as well as the stimulate hepatocytes proliferation in the D-GalN/BMSCs group compared to the D-GalN/D-hanks group(p＜0.001).
CONCLUSIONS The transplantation of BMSCs effectively contribute to the repair of the severely acute liver injury in D-GalN-induced rabbits.Injection of BMSCs directly into the liver is the simple route of administration in experimental model.
引文
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