Clonal expansion of hepatic progenitor cells and differentiation into hepatocyte-like cells
Clonal expansion of hepatic progenitor cells and differentiation into hepatocyte-like cells
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肝祖细胞的克隆扩增并分化为肝细胞样细胞
DOI：
10.1111/dgd.12596
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发表时间：
2019-04-01
影响因子：
2.5
通讯作者：
Wu, Zhongjun
中科院分区：
文献类型：
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作者：
Liu, Wenbin;Wang, Yujia;Wu, Zhongjun
成人肝脏中的肝祖细胞（HPCs）在肝脏疾病的治疗中具有广阔的应用前景。成年小鼠中胆汁来源的HPC群体的特征在于干细胞标志物Sry（性别决定区Y）-box 9（SOX 9）和胆汁标志物细胞角蛋白7（CK 7）的共表达。然而，在成人健康肝脏中分离这些HPC而不进行任何选择程序仍然是该领域的一大挑战。在此，我们建立了一种简单有效的方法，在体外分离和扩增CK 7（+）SOX 9（+）HPC作为克隆，我们获得了一个稳定的，很大程度上可扩展的细胞来源。然后，在肝细胞生长因子（HGF）和成纤维细胞生长因子9（FGF 9）存在下，在体外和体内进一步诱导CK 7（+）SOX 9（+）祖细胞分化为表达成熟肝细胞标志物白蛋白（Alb）和肝细胞核因子4 α（HNF 4 α）的肝细胞样细胞。此外，我们发现HPC对转化生长因子-β（TGF-β）信号高度敏感。总的来说，我们通过一种简单有效的方法从成年小鼠肝脏中鉴定并收获了CK 7（+）SOX 9（+）祖细胞群。这种HPC群体的探索提供了产生肝细胞样细胞的替代策略，用于急性和慢性肝脏疾病的基于细胞的治疗。
Hepatic progenitor cells (HPCs) in adult liver are promising for treatment of liver diseases. A biliary-derived HPC population in adult mice has been characterized by co-expression of stem cell marker Sry (sex determining region Y)-box 9 (SOX9) and biliary marker cytokeratin 7 (CK7). However, isolation of these HPCs in adult healthy liver without any selection procedures remains a big challenge in this field. Here, by establishing a simple and efficient method to isolate and expand the CK7(+)SOX9(+) HPCs in vitro as clones, we acquired a stable and largely scalable cell source. The CK7(+)SOX9(+) progenitor cells were then further induced to differentiate into hepatocyte-like cells with expression of mature hepatocyte markers albumin (Alb) and hepatocyte nuclear factor 4 alpha (HNF4 alpha), both in vitro and in vivo in the presence of hepatocyte growth factor (HGF) and fibroblast growth factor 9 (FGF9). Furthermore, we found that the HPCs are highly responsive to transforming growth factor-beta (TGF-beta) signals. Collectively, we identified and harvested a CK7(+)SOX9(+) progenitor cell population from adult mouse liver by a simple and efficient approach. The exploration of this HPC population offers an alternative strategy of generating hepatocyte-like cells for cell-based therapies of acute and chronic liver disorders.