Clonal tracing of Sox9+ liver progenitors in mouse oval cell injury.
Clonal tracing of Sox9+ liver progenitors in mouse oval cell injury.
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DOI：
10.1002/hep.27084
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发表时间：
2014-07
期刊：
影响因子：
13.5
通讯作者：
Grompe, Markus
中科院分区：
文献类型：
--
作者：
Tarlow, Branden D.;Finegold, Milton J.;Grompe, Markus
增殖管，称为“卵圆细胞”，长期以来被认为具有双潜能，即在慢性肝损伤期间既产生胆管又产生肝细胞。卵圆细胞的前体被认为是兼性肝干细胞（LSC）。最近的谱系追踪实验表明，LSC 是 Sox9+，可以在多种情况下替代大量肝细胞。然而，Sox9+细胞和两种上皮肝谱系之间没有建立克隆关系。我们用多色荧光五彩纸屑报告器低密度标记了 Sox9+ 小鼠肝细胞。类器官的形成验证了标记群体的祖细胞活性。使用组织学和 FACS 在多个卵圆细胞损伤模型中追踪 Sox9+ 细胞。令人惊讶的是，在任何实验中都只发现了含有肝细胞和卵圆细胞的罕见克隆。定量分析表明，即使在经典的卵圆细胞损伤模型中，Sox9+ 细胞对肝细胞库的贡献也很小（<1%）。相比之下，克隆标记的成熟肝细胞在所有经典的小鼠卵圆细胞激活损伤中表现出自我更新的能力。用于追踪肝细胞和非实质细胞的肝细胞嵌合体模型也证明了小鼠卵圆细胞损伤模型中肝细胞驱动的再生的普遍性。 Sox9+ 导管祖细胞产生克隆卵圆细胞增殖和双能类器官，但很少在体内产生肝细胞。在卵圆细胞激活的原型小鼠模型中，肝细胞本身是新实质细胞的主要来源。
Proliferating ducts, termed “oval cells”, have long thought to be bipotential, i.e. produce both biliary ducts and hepatocytes during chronic liver injury. The precursor to oval cells is considered to be a facultative liver stem cell (LSC). Recent lineage tracing experiments indicated that the LSC is Sox9+ and can replace the bulk of hepatocyte mass in several settings. However, no clonal relationship between Sox9+ cells and the two epithelial liver lineages was established. We labeled Sox9+ mouse liver cells at low density with a multicolor fluorescent confetti reporter. Organoid formation validated the progenitor activity of the labeled population. Sox9+ cells were traced in multiple oval cell injury models using both histology and FACS. Surprisingly, only rare clones containing both hepatocytes and oval cells were found in any experiment. Quantitative analysis showed that Sox9+ cells contributed only minimally (<1%) to the hepatocyte pool, even in classic oval cell injury models. In contrast, clonally marked mature hepatocytes demonstrated the ability to self-renew in all classic mouse oval cell activation injuries. A hepatocyte chimera model to trace hepatocytes and non-parenchymal cells also demonstrated the prevalence of hepatocyte-driven regeneration in mouse oval cell injury models. Sox9+ ductal progenitor cells give rise to clonal oval cell proliferation and bipotential organoids but rarely produce hepatocytes in vivo. Hepatocytes themselves are the predominant source of new parenchyma cells in prototypical mouse models of oval cell activation.
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