Retinoic acid signalling induces the differentiation of mouse fetal liver-derived hepatic progenitor cells
Retinoic acid signalling induces the differentiation of mouse fetal liver-derived hepatic progenitor cells
复制标题
视黄酸信号诱导小鼠胎肝源性肝祖细胞的分化
DOI：
10.1111/j.1478-3231.2009.02111.x
复制
发表时间：
2009-11-01
影响因子：
6.7
通讯作者：
Tang, Ni
中科院分区：
文献类型：
--
作者：
Huang, Jiayi;Bi, Yang;Tang, Ni
背景肝祖细胞（Hepatic progenitor cells，HPCs）可从胎肝和肝外组织中分离获得.维甲酸（RA）信号在发展中起着重要的作用，虽然RA信号在肝脏特异性祖细胞的作用知之甚少。AimsWe试图确定RA在调节肝分化的作用。通过逆转录-聚合酶链反应和免疫荧光染色评估肝脏标志物表达。建立了来源于小鼠胚胎第14.5天（E14.5）肝脏（aka，HP14.5）的可逆永生化HPC。白蛋白启动子驱动的报告基因（Alb-GLuc）用于监测肝分化。糖原的合成作为一个标志物进行了测定终末hepatic differentiation.ResultsRetinoic酸受体（RAR）-α，维甲酸X受体（RXR）-α和RXR-γ表达在E12.5出生后第28天的肝脏样本。RAR-β和RXR-β的表达在围产期较低，而RAR-γ在产前组织中检测不到，并在出生后增加。视网膜脱氢酶1和2（Raldh 1和Raldh 2）在所有组织中表达，而Raldh 3在产前样品中弱表达，但出生后很容易检测到。核受体辅抑制因子在所有组织中均高度表达，而核辅激活因子的表达在围产期组织中降低，出生后增加。HP14.5细胞表达高水平的早期肝干细胞标志物。在HP14.5中很容易检测到RA信号传导组分和辅助调节因子的表达。RA可诱导Alb-GLuc活性和晚期肝细胞标志物。RA被进一步证明诱导糖原合成在HP14.5细胞，一个重要的功能成熟hepatocyte.ConclusionsOur结果强烈表明，RA信号可能发挥重要作用，在调节肝分化。
BackgroundHepatic progenitor cells (HPCs) can be isolated from fetal liver and extrahepatic tissues. Retinoic acid (RA) signalling plays an important role in development, although the role of RA signalling in liver-specific progenitors is poorly understood.AimsWe sought to determine the role of RA in regulating hepatic differentiation.MethodsRNA was isolated from liver tissues of various developmental stages. Liver marker expression was assessed by reverse transcriptase-polymerase chain reaction and immunofluorescence staining. Reversibly immortalized HPCs derived from mouse embryonic day 14.5 (E14.5) liver (aka, HP14.5) were established. Albumin promoter-driven reporter (Alb-GLuc) was used to monitor hepatic differentiation. Glycogen synthesis was assayed as a marker for terminal hepatic differentiation.ResultsRetinoic acid receptor (RAR)-alpha, retinoid X receptor (RXR)-alpha and RXR-gamma expressed in E12.5 to postnatal day 28 liver samples. Expression of RAR-beta and RXR-beta was low perinatally, whereas RAR-gamma was undetectable in prenatal tissues and increased postnatally. Retinal dehydrogenase 1 and 2 (Raldh1 and Raldh2) were expressed in all tissues, while Raldh3 was weakly expressed in prenatal samples but was readily detected postnatally. Nuclear receptor corepressors were highly expressed in all tissues, while expression of nuclear co-activators decreased in perinatal tissues and increased after birth. HP14.5 cells expressed high levels of early liver stem cell markers. Expression of RA signalling components and coregulators was readily detected in HP14.5. RA was shown to induce Alb-GLuc activity and late hepatocyte markers. RA was further shown to induce glycogen synthesis in HP14.5 cells, an important function of mature hepatocytes.ConclusionsOur results strongly suggest that RA signalling may play an important role in regulating hepatic differentiation.