Human mesenchymal stem cells as a two-edged sword in hepatic regenerative medicine: engraftment and hepatocyte differentiation versus profibrogenic potential
Human mesenchymal stem cells as a two-edged sword in hepatic regenerative medicine: engraftment and hepatocyte differentiation versus profibrogenic potential
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DOI：
10.1136/gut.2006.111617
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发表时间：
2008-02-01
期刊：
影响因子：
24.5
通讯作者：
Parola, M.
中科院分区：
文献类型：
--
作者：
Di Bonzo, L. Valfre;Ferrero, I.;Parola, M.
背景和目的：骨髓间充质干细胞（MSCs）可能具有在体内和体外向肝细胞分化的潜力。我们研究了移植的人间充质干细胞（hMSCs）是否可以移植到非肥胖糖尿病严重联合免疫缺陷（NOD/SCID）小鼠的肝脏并分化为肝系细胞。方法：将体外扩增的、高度纯化的、具有功能活性的hMSCs从骨髓中移植（尾静脉）到亚致死照射的NOD/SCID小鼠中，这些小鼠要么暴露于急性肝损伤，要么接受慢性损伤（分别为单次或慢性腹腔注射CCl4）。分析嵌合肝脏中人类转录本和抗原的表达。结果：在正常和急性损伤的NOD/SCID小鼠中，人源性细胞的肝移植量非常低，而在慢性损伤的小鼠中，人源性细胞的肝移植量明显增加。然而，肝细胞分化相对罕见，仅限于少量细胞（范围小于0.1%至0.23%），证实了正常或损伤肝脏中甲胎蛋白、CK18、CK19和白蛋白的人类转录物水平非常低或无法检测到。最后，大量人源性细胞表现出肌成纤维细胞样形态。结论：移植的hMSC有可能迁移到正常和损伤的肝实质，特别是在慢性损伤的情况下，但分化为肝细胞样细胞是罕见的事件，hMSC移植的促纤维化潜力不应被低估。
Background and aim: Mesenchymal stem cells from bone marrow (MSCs) may have the potential to differentiate in vitro and in vivo into hepatocytes. We investigated whether transplanted human MSCs (hMSCs) may engraft the liver of non-obese diabetic severe combined immuno-deficient (NOD/SCID) mice and differentiate into cells of hepatic lineage.Methods: Ex vivo expanded, highly purified and functionally active hMSCs from bone marrow were transplanted (caudal vein) in sublethally irradiated NOD/SCID mice that were either exposed or not to acute liver injury or submitted to a protocol of chronic injury (single or chronic intraperitoneal injection of CCl4, respectively). Chimeric livers were analysed for expression of human transcripts and antigens.Results: Liver engraftment of cells of human origin was very low in normal and acutely injured NOD/SCID mice with significantly higher numbers found in chronically injured livers. However, hepatocellular differentiation was relatively rare, limited to a low number of cells (ranging from less than 0.1% to 0.23%) as confirmed by very low or not detectable levels of human transcripts for alpha-fetoprotein, CK18, CK19 and albumin in either normal or injured livers. Finally, a significant number of cells of human origin exhibited a myofibroblast-like morphology.Conclusions: Transplanted hMSCs have the potential to migrate into normal and injured liver parenchyma, particularly under conditions of chronic injury, but differentiation into hepatocyte-like cells is a rare event and pro-fibrogenic potential of hMSC transplant should be not under-evaluated.