Identification and characterization of vitamin a-storing cells in fetal liver: Implications for functional importance of hepatic stellate cells in liver development and Hematopoiesis
Identification and characterization of vitamin a-storing cells in fetal liver: Implications for functional importance of hepatic stellate cells in liver development and Hematopoiesis
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DOI：
10.1634/stemcells.2006-0316
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发表时间：
2007-09-01
期刊：
影响因子：
5.2
通讯作者：
Reid, Lola M.
中科院分区：
文献类型：
--
作者：
Kubota, Hiroshi;Yao, Hsin-Lei;Reid, Lola M.
肝星状细胞(HpSTCs)是成人肝纤维化的主要调节细胞。然而，它们在胎肝中的早期发育在很大程度上是未知的。为了鉴定肝脏中的胎儿HpSTCs，其中肝脏发育和造血同时发生，我们采用以维生素A为重点的策略，测定了大鼠胎肝HpSTCs的表型特征。在细胞质中储存维生素A是HpSTCs的独特特征，允许使用流式细胞术通过紫外光激发时维生素A特异的自身荧光(Va(+))来识别它们。肝脏Va(+)细胞群的表型为rT1a(-)细胞间黏附分子(ICAM)-1(+)血管细胞黏附分子(VCAM)-1(+)-β3-整合素(+)。尽管发现了非特异性自身荧光细胞，具有RT1A(-)ICAM-1(+)VCAM-1(+)的抗原性，但它们是β3-整合素(-)，被证明是肝母细胞，具有双功能的肝实质前体细胞。除了表达经典的HpSTC标志物外，Va(+)细胞还能够在含有白血病抑制因子的无血清激素定义的培养液中持续增殖，这被发现是其复制的关键因素。这些结果表明，Va(+)细胞是胎儿HpSTCs，具有广泛的增殖活性。此外，Va(+)细胞强烈表达肝细胞生长因子、基质衍生因子-1α和HLX(同源盒转录因子)，表明它们在肝脏发育和造血中发挥重要作用。分离和扩增胎儿HpSTCs的能力使我们能够进一步研究它们在肝脏早期发育中的作用，并有助于识别可能与肝脏疾病潜在相关的新信号。
Hepatic stellate cells (HpSTCs) are major regulators of hepatic fibrogenesis in adults. However, their early development in fetal liver is largely unknown. To characterize fetal HpSTCs in the liver, in which hepatic development and hematopoiesis occur in parallel, we determined the phenotypic characteristics of HpSTCs from rat fetal livers, using a strategy focused on vitamin A. Storage of vitamin A in the cytoplasm is a unique characteristic of HpSTCs, permitting identification of them by vitamin A-specific autofluorescence (vA(+)) when excited with UV light using flow cytometry. A characteristic vA(+) cell population was identified in liver as early as 13 days post coitum; it had a surface phenotype of RT1A(-) intercellular adhesion molecule (ICAM)-1(+) vascular cell adhesion molecule (VCAM)-1(+) beta 3-integrin(+). Although nonspecific autofluorescent cells were found with the antigenic profile of RT1A(-) ICAM-1(+) VCAM-1(+), they were beta 3-integrin(-) and proved to be hepatoblasts, bipotent hepatic parenchymal progenitors. In addition to expression of classic HpSTC markers, the vA(+) cells were able to proliferate continuously in a serum-free hormonally defined medium containing leukemia inhibitory factor, which was found to be a key factor for their replication. These results demonstrated that the vA(+) cells are fetal HpSTCs with extensive proliferative activity. Furthermore, the vA(+) cells strongly express hepatocyte growth factor, stromal-derived factor-1 alpha, and Hlx (homeobox transcription factor), indicating that they play important roles for hepatic development and hematopoiesis. The abilities to isolate and expand fetal HpSTCs enable further investigation into their roles in early liver development and facilitate identification of possibly novel signals of potential relevance for liver diseases.