The liver as a stem cell and lineage system.
The liver as a stem cell and lineage system.
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肝脏作为干细胞和谱系系统。
DOI：
10.1152/ajpgi.1992.263.2.g139
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发表时间：
1992
期刊：
影响因子：
--
通讯作者：
Reid,LM
中科院分区：
文献类型：
--
作者：
Sigal,SH;Brill,S;Fiorino,AS;Reid,LM
我们认为肝脏是一个干细胞和谱系系统，与骨髓、肠道和表皮中的谱系有许多相似之处，只是在动力学上有所不同。它们都由三个部分组成：慢周期干细胞部分，细胞表现为胎儿表型，对损伤反应缓慢；扩增部分，中等表型细胞对再生刺激或急性损伤反应迅速；末端分化部分，细胞分化增加，逐渐失去分裂能力。在所有的系统中，无论是缓慢的还是快速的，不同的隔室都位于一个极化的组织中，与细胞外基质的化学成分的梯度有关，并显示出与血统位置相关的生长反应、基因表达、药理和毒理反应以及对病毒和辐射的反应。一般来说，已知的癌基因选择性地杀伤分化室中的细胞，诱导干细胞和/或扩增室中细胞的慢性再生反应。肿瘤是由激活的干细胞或早期前体细胞随后转化而来的。血统模型的证据包括细胞大小、倍体、生长潜力以及沿着正弦板的肝实质中的抗原和基因表达的梯度的数据。对这种异质性的传统解释是，它代表了细胞对由血流方向决定的不断变化的正弦微环境的适应。然而，我们回顾了现有的数据，并建议它更容易支持一种谱系模型，该模型涉及一个成熟过程，从门静脉周围区域的干细胞和前体细胞开始，以靠近中心静脉的感觉实质结束。对肝脏表型异质性的研究，对肝脏胚胎学的研究，以及对肝脏对化学和病毒致癌物质的反应的分析，都为这一理论提供了支持。这些致癌物质可以诱导具有椭圆形细胞核的小细胞快速增殖，目前被认为与肝脏干细胞关系密切。该谱系模型为肝脏生物学和疾病的许多方面提供了清晰和深入的信息，包括体外实质培养的有限增殖能力、肝脏再生、基因表达、病毒感染、肝细胞癌、肝细胞移植和衰老。
We propose that the liver is a stem cell and lineage system with many parallels to lineages in the bone marrow, gut, and epidermis, varying from them only in kinetics. All are organized with three compartments: a slow cycling stem cell compartment with cells expressing a fetal phenotype and responding slowly to injury; an amplification compartment with cells of intermediate phenotype rapidly proliferating in response to regenerative stimuli or acute injuries; and a terminal differentiation compartment in which cells increasingly differentiate and gradually lose their ability to divide. In all systems, both those with slow or rapid kinetics, the various compartments are positioned in a polarized organization, are associated with a gradient in the chemistry of the extracellular matrix, and show lineage-position-dependent growth responses, gene expression, pharmacological and toxicological responses, and reaction to viruses and radiation. In general, known oncogens selectively kill cells in the differentiation compartment inducing chronic regenerative responses of the cells in stem cell and/or amplification compartment. Tumors arise by subsequent transformation of the activated stem cells or early precursor cells. The evidence for a lineage model consists of the data implicating gradients in cell size, ploidy, growth potential, and antigenic and gene expression in the liver parenchyma along the sinusoidal plates. The traditional explanation for this heterogeneity is that it represents adaption of cells to a changing sinusoidal microenvironment dictated by the direction of blood flow. However, we review the extant data and suggest that it more readily supports a lineage model involving a maturation process beginning with stem cells and precursors in the periportal zone and ending with sensescing parenchyma near the central vein. Support for this theory is provided by the studies on phenotypic heterogeneity in liver, investigations into the embryology of the liver, and analyses of the responses of liver to chemical and viral oncogens that induce rapid proliferation of small cells with oval-shaped nuclei, "oval cells," now thought to be closely related to liver stem cells. The lineage model provides clarity and insights into many aspects of liver biology and disease including the limited proliferative ability of in vitro parenchymal cultures, liver regeneration, gene expression, viral infection, hepatocellular carcinogenesis, liver cell transplantation, and aging.