Mature hepatocytes exhibit unexpected plasticity by direct dedifferentiation into liver progenitor cells in culture.
Mature hepatocytes exhibit unexpected plasticity by direct dedifferentiation into liver progenitor cells in culture.
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DOI：
10.1002/hep.24712
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发表时间：
2012-02
期刊：
影响因子：
13.5
通讯作者：
Sahin, M. Behnan
中科院分区：
文献类型：
--
作者：
Chen, Yixin;Wong, Philip P.;Sjeklocha, Lucas;Steer, Clifford J.;Sahin, M. Behnan
虽然已经有许多报道描述了从成人肝脏中分离肝祖细胞，但它们的确切来源尚未明确定义;成熟肝细胞作为肝祖细胞库的直接贡献者所发挥的作用在很大程度上仍然未知。在这里，我们报告了强有力的证据表明，培养中的成熟肝细胞有能力去分化成一个成年肝祖细胞的人口没有遗传或表观遗传操作。通过使用高度纯化的成熟肝细胞，这是从未经处理的，健康的大鼠肝脏和荧光染料PKH 2标记，我们发现，培养中的肝细胞产生了一个群体的PKH 2阳性肝祖细胞。这些细胞，肝源性祖细胞或LDPCS，与卵圆细胞具有表型相似性，先前报道能够在培养物和动物中形成成熟肝细胞。在去分化培养过程中的不同时间点进行的研究表明，肝细胞在一周内通过短暂的卵圆细胞样阶段迅速转化为肝祖细胞。这一发现得到了谱系追踪研究的支持，该研究涉及仅在肝细胞中表达β-半乳糖苷酶的双转基因AlbuminCreXRosa 26小鼠。用从这些小鼠获得的肝细胞建立的培养物导致产生β-半乳糖苷酶阳性肝祖细胞，证明它们是成熟肝细胞的直接去分化产物。此外，这些祖细胞分化成肝细胞在体内移植到大鼠进行了retrorsine预处理和部分肝切除术。我们的研究为成熟肝细胞在培养中去分化为祖细胞的意外可塑性提供了强有力的证据;这可能对需要肝脏或肝细胞移植的肝脏疾病的治疗产生重大影响。
Although there have been numerous reports describing the isolation of liver progenitor cells from adult liver, their exact origin has not been clearly defined; and the role played by mature hepatocytes as direct contributors to the hepatic progenitor cell pool has remained largely unknown. Here we report strong evidence that mature hepatocytes in culture have the capacity to dedifferentiate into a population of adult liver progenitors without genetic or epigenetic manipulations. By using highly-purified mature hepatocytes, which were obtained from untreated, healthy rat liver and labeled with fluorescent dye PKH2, we found that hepatocytes in culture gave rise to a population of PKH2-positive liver progenitor cells. These cells, Liver Derived Progenitor Cells or LDPCS, which share phenotypic similarities with oval cells, were previously reported to be capable of forming mature hepatocytes both in culture and in animals. Studies done at various time points during the course of dedifferentiation cultures revealed that hepatocytes rapidly transformed into liver progenitors within one week through a transient oval cell-like stage. This finding was supported by lineage-tracing studies involving double-transgenic AlbuminCreXRosa26 mice expressing β-galactosidase exclusively in hepatocytes. Cultures set up with hepatocytes obtained from these mice resulted in generation of β-galactosidase-positive liver progenitor cells demonstrating that they were a direct dedifferentiation product of mature hepatocytes. Additionally, these progenitors differentiated into hepatocytes in vivo when transplanted into rats that had undergone retrorsine pretreatment and partial hepatectomy. Our studies provide strong evidence for the unexpected plasticity of mature hepatocytes to dedifferentiate into progenitor cells in culture; and this may potentially have a significant impact on the treatment of liver diseases requiring liver or hepatocyte transplantation.
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影响因子：
--
作者：
Takashimizu I;Tanaka Y;Yoshie S;Kano Y;Ichikawa H;Cui L;Ogiwara N;Johkura K;Sasaki K
通讯作者：
Sasaki K
影响因子：
13.5
作者：
Theise, ND;Nimmakayalu, M;Krause, DS
通讯作者：
Krause, DS
影响因子：
4.6
作者：
Chen, Yixin;Zhou, Hongchao;Sahin, M. Behnan
通讯作者：
Sahin, M. Behnan
影响因子：
13.5
作者：
Theise, ND;Badve, S;Krause, DS
通讯作者：
Krause, DS
影响因子：
4.8
作者：
Kaimori, Aki;Potter, James;Koteish, Ayman
通讯作者：
Koteish, Ayman