Implementation of Cord- Blood Derived Unrestricted Somatic Stem Cells in the Regeneration of two Experimental Models: Carbon Tetrachloride and S. Mansoni Induced Liver Fibrosis

RAN Pub Date : 2016-04-01 DOI:10.11159/NDDTE16.121
M. Kamel, Z. Demerdash, H. El-Baz, S. Hassan, Faten Salah, W. Mansour, Olfat Hamamm
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Abstract

Extended Abstract Liver fibrosis is the wound-healing response of the liver to chronic injury it is very important to investigate different treatments and therapies for cirrhosis as the liver is one of the target organs for which stem cell-based therapeutics is very promising. In this study, Isolation, propagation, and characterization of unrestricted somatic stem cells (USSCs) from cord blood (CB) samples were performed and induced to differentiate into osteoblasts, adipocytes and hepatocyte-like cells. The therapeutic potentiality of USSCs in two experimental models of chronic liver injury was evaluated. First experimental model (30 mice): Ten Schistosoma mansoni infected mice were intravenously injected with USSCs 1×10 cell/mouse. Ten were infected untreated (pathological control) and 10 healthy mice (negative control). 2nd experimental model (30 hamsters): Twenty were injected with repeated doses of carbon tetrachloride Sigma-Aldrich Chemical Co. (St Louis, Missouri, USA) to induce liver fibrosis; 10 were treated with intrahepatic injection of 3x10 USSCs and the other 10 were untreated pathological control. Ten healthy hamsters served as negative control. Animals were sacrificed 12 weeks post transplantation, and their liver sections were examined for detection of human hepatocyte-like cells by immunohistochemical staining. Moreover, liver sections were examined for fibrosis levels. Sera of sacrificed animals were tested for liver functions. CB USSCs, with fibroblast-like morphology, expressed high levels of CD44, CD90, CD73 and CD105 and were negative for CD34, CD45, and HLA-DR. USSCs showed high expression of transcripts for Oct4 and Sox2 and were in vitro differentiated into osteoblasts, adipocytes, and hepatocyte-like cells. In both models transplantation of CBUSSCs resulted in engraftment of the fibrosed livers with newly formed hepatocytes evidenced by positive immunostaining with human Hep Par1, α-fetoprotein, CK-18, CK-7 and OV6. Transplanted liver sections showed diminished hepatic fibrosis with significantly lower fibrotic index as well as significantly improved liver functions compared to the pathological control (p<0.001). Conclusion These data provide hope that human CBderived USSCs are introduced as multipotent stem cells with great potentiality in regenerative medicine & strengthens the concept of cellular therapy for the treatment of liver fibrosis. This work is extracted from the project 1410 supported by the Science and Technology Development Funds (STDF), Cairo, Egypt.
脐带血来源的非限制性体细胞干细胞在四氯化碳和S. Mansoni诱导肝纤维化两种实验模型再生中的应用
肝纤维化是肝脏对慢性损伤的创面愈合反应,肝脏是干细胞治疗非常有前景的靶器官之一,研究肝硬化的不同治疗方法具有重要意义。在这项研究中,从脐带血(CB)样本中分离、繁殖和鉴定非限制性体细胞干细胞(USSCs),并诱导其分化为成骨细胞、脂肪细胞和肝细胞样细胞。研究了两种慢性肝损伤实验模型中USSCs的治疗潜力。第一个实验模型(30只小鼠):10只感染曼氏血吸虫的小鼠静脉注射USSCs 1×10细胞/小鼠。10只感染未处理小鼠(病理对照组),10只健康小鼠(阴性对照组)。第二组实验模型(30只):20只小鼠注射重复剂量四氯化碳Sigma-Aldrich Chemical Co. (St Louis, Missouri, USA)诱导肝纤维化;肝内注射3x10 USSCs治疗10只,病理对照10只。10只健康仓鼠作为阴性对照。移植后12周处死动物,用免疫组化染色法检查其肝脏切片,检测人肝细胞样细胞。此外,肝脏切片检查纤维化水平。对牺牲动物血清进行肝功能检测。CB USSCs具有成纤维细胞样形态,表达高水平的CD44、CD90、CD73和CD105, CD34、CD45和HLA-DR呈阴性。USSCs高表达Oct4和Sox2转录本,并在体外分化为成骨细胞、脂肪细胞和肝细胞样细胞。在这两种模型中,移植CBUSSCs可使纤维化肝脏植入新形成的肝细胞,人Hep Par1、α-胎蛋白、CK-18、CK-7和OV6免疫染色阳性。与病理对照组相比,移植肝切片显示肝纤维化减轻,纤维化指数明显降低,肝功能明显改善(p<0.001)。结论这些数据为人CBderived USSCs作为具有巨大再生医学潜力的多能干细胞的引入提供了希望,并加强了细胞疗法治疗肝纤维化的概念。本文摘自埃及开罗科技发展基金(STDF)项目1410。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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