Kupffer cell depletion by gadolinium chloride enhances liver regeneration after partial hepatectomy in rats
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Although previous work suggests that tumor necrosis factor-alpha (TNF) promotes liver regeneration after partial hepatectomy (PH), the source of TNF is unknown. If Kupffer cells release TNF after PH, then Kupffer cell depletion by gadolinium chloride (GdCl) should inhibit liver regeneration. To test this hypothesis, cytokine expression and regenerative events were compared in GdCl-treated and control rats. Functional assays and Northern blot analysis of a Kupffer cell-specific mRNA confirmed that GdCl depleted Kupffer cells. Despite this, semiquantitative reverse transcription-polymerase chain reaction analysis of total hepatic RNA showed six- to eightfold higher levels of TNF transcripts in GdCl-treated rats. In this group, PH caused 12-to 16-fold greater induction of interleukin-6, a TNF-inducible cytokine, and two- to threefold greater induction of several cytokine-regulated genes (c-jun, C/EBP-beta, and C/EBP-delta). GdCl also amplified regeneration-associated increases in the DNA binding activity of AP-1, a growth regulatory transcription factor. Furthermore, hepatic incorporation of [3H]thymidine, expression of the S-phase antigen, proliferating cell nuclear antigen, and the hepatocyte mitotic index were each significantly greater in GdCl-treated rats. Thus, although GdCl causes Kupffer cell depletion, it does not decrease liver TNF and actually enhances liver regeneration after PH.Keywords:
Liver Regeneration
Kupffer cell
This chapter contains sections titled: Why does the liver need to regenerate? Experimental models and clinical settings Cellular kinetics during liver regeneration after partial hepatectomy Functional and structural changes in liver histology during regeneration General functional aspects of cell signaling during liver regeneration Extracellular signals leading liver into regeneration Intracellular events occurring during regeneration Extracellular matrix changes and angiogenesis Paracrine signaling interactions between different cell types during liver regeneration What starts and ends liver regeneration: a semispeculative view Alternative pathways to liver regeneration: oval cells and stem cells Clinical aspects of liver regeneration: cirrhosis and fulminant hepatitis Augmentative hepatomegaly Conclusions References
Liver Regeneration
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The liver has great regeneration capacity.As a response to injury(partial hepatectomy,injury by chemical toxins and virus),liver regeneration is stimulated to repair the damaged tissue and rival injury by.proliferation and differentiation of parenchymal cell and nonparenchymal cell.Liver regeneration is a complicated and special process of cell proliferation,its regulatory mechanism is also very complicated.So in this review,we discuss these aspects of liver regeneration.
Liver Regeneration
Parenchyma
Liver parenchyma
Liver cell
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In the absence of adequate compensatory regeneration, overwhelming liver damage can cause acute liver failure (ALF) and death without emergent liver transplantation (LT). Auxiliary LT produces satisfactory outcomes in this setting, with the prospect of native liver regeneration sustaining long-term survival. Since animal models only partially recapitulate human liver regeneration, we investigated the molecular mechanisms controlling it in this unique LT setting, as an exemplar of human liver regeneration. We demonstrate coordinated changes in expression of microRNA (miRNA) during regeneration that drive proliferation, innate immunity and angiogenesis. In contrast, failed regeneration in a similar cohort is associated with distinct miRNA enforcing cell cycle inhibition and DNA methylation. The miRNA expression associated with successful or failed regeneration when recapitulated in vitro, triggered expression of cardinal regeneration-linked genes promoting cell cycle entry or inhibition, respectively. Furthermore, inhibition of miRNA 150, 663 and 503, whose downregulation is associated with successful regeneration, induced cell proliferation which a key determinant of successful regeneration. Our data indicate that human liver regeneration may be orchestrated by distinct miRNA controlling key regeneration-linked processes including hepatocyte proliferation. To our knowledge this is the first characterization of molecular processes associated with human liver regeneration.
Liver Regeneration
Cell fate determination
Expression (computer science)
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【Objective】To investigate the relationship between liver regeneration and pancreas regeneration in rats.【Method】 20 SD rats were randomized into 4 groups:Establish 15 male SD rats model of liver regeneration by 58% hepatectomy.Control group5 SD rats only to switch abdominal operation.After 2 weeks,observe the phenomenon of the liver regeneration and pancreas regeneration by immunolhistochemistry,the regeneration phenomenon is not observed in control group.【Result】Liver and pancreas have different levels of regeneration phenomenon in experimental group.【Conclusion】 When the liver in the regeneration of active cases,the inducing factor will also cause regeneration of the pancreas
Liver Regeneration
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瞄准：为了在 Kupffer 房间上观察肝新生(ALR ) 的 augmenter 的效果并且决定 ALR 是否支持 hepatocyte，增长由 Kupffer 房间导致了。方法：Kupffer 房间和 hepatocytes 是有教养的在试管内， recombinant 老鼠 ALR (rrALR ) 的各种各样的集中被增加。3H-thymidine， BrdU 和 3H 白氨酸加入在有教养的 Kupffer 房间和 hepatocytes 是坚定的，在 Kupffer 房间调节的 hepatocytes，并且在联系媒介。rrALR 被 iodination 标记并且过去常在 Kupffer 由 Scatchard 分析决定它的有约束力的活动房间和首先有教养的老鼠 hepatocytes。结果：rrALR 以一种 non-concentration-dependent 方式在房间并且在媒介在 Kupffer 房间和蛋白质合成刺激了 DNA 复制。效果在 1 microg/L ALR 的集中是重要的。然而，当 hepatocytes 是有教养的， Kupffer 房间媒介在在 1 microg/L ALR 的集中显著地增加的 hepatocytes 由 ALR， DNA 复制和蛋白质合成调节了时， rrALR 没在首先有教养的 hepatocytes 上有效果。当 ALR 集中被增加时，它 hepatocyte 增长上的效果减少了到基础水平。Scatchard 分析在老鼠 Kupffer 房间与 0.883 nmol/L 的一个离解常数(Kd ) 和 126.1 pmol/g 蛋白质的一个最大的有约束力的能力(Bmax ) 显示了高亲密关系受体的一个单个班的存在。结论：ALR 能支持 Kupffer 房间导致的 hepatocyte 增长，它与 ALR 的集中被联系，建议 Kupffer 房间起在肝新生的一个双作用。
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Liver Regeneration
Liver cytology
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Abstract The liver is a highly regenerative organ, but its regenerative capacity is compromised in severe liver diseases. Hepatocyte-driven liver regeneration that involves the proliferation of preexisting hepatocytes is a primary regeneration mode. On the other hand, liver progenitor cell (LPC)-driven liver regeneration that involves dedifferentiation of biliary epithelial cells or hepatocytes into LPCs, LPC proliferation, and subsequent differentiation of LPCs into hepatocytes is a secondary mode. This secondary mode plays a significant role in liver regeneration when the primary mode does not effectively work, as observed in severe liver injury settings. Thus, promoting LPC-driven liver regeneration may be clinically beneficial to patients with severe liver diseases. In this review, we describe the current understanding of LPC-driven liver regeneration by exploring current knowledge on the activation, origin, and roles of LPCs during regeneration. We also describe animal models used to study LPC-driven liver regeneration, given their potential to further deepen our understanding of the regeneration process. This understanding will eventually contribute to developing strategies to promote LPC-driven liver regeneration in patients with severe liver diseases.
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Liver cell
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Liver regeneration has been studied for many decades, and the mechanisms underlying regeneration of normal liver following resection are well described. However, no less relevant is the study of mechanisms that disrupt the process of liver regeneration. First of all, a violation of liver regeneration can occur in the presence of concomitant hepatic pathology, which is a key factor reducing the liver’s regenerative potential. Understanding these mechanisms could enable the rational targeting of specific therapies to either reduce the factors inhibiting regeneration or to directly stimulate liver regeneration. This review describes the known mechanisms of normal liver regeneration and factors that reduce its regenerative potential, primarily at the level of hepatocyte metabolism, in the presence of concomitant hepatic pathology. We also briefly discuss promising strategies for stimulating liver regeneration and those concerning methods for assessing the regenerative potential of the liver, especially intraoperatively.
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Regenerative process
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Abstract Using cytofluorimetry and absorptional cytophotometry, hepatocyte DNA and total protein contents were measured in intact and cirrhotic rats in 1, 3 and 6 months after partial hepatectomy (PH). It has been found that within one month of intact rat liver regeneration the level of hepatocyte ploidy rised by 25% to remain elevated for the next 6 months. This was due mainly to reducing the number of cells with diploid nuclei (2c 2-fold, 2c x 2 - 6.6-fold) and to rising the number of octaploid hepatocytes. In cirrhotic animals the ploidy level in hepatocytes increased in 3 months after PH, and decreased by 15% in 6 months. The number of hepatocytes with diploid nuclei (2c and 2c x 2) increased within 3-6 months in both control and cirrhotic rats. The protein content per diploid hepatocyte rised by 30% within 3-6 months of liver regeneration after PH. Special calculations have shown that within 3 months after PH the increase in the liver mass of control and cirrhotic rats was due completely to hepatocyte DNA synthesis, i. e. proliferation and polyploidization. Within the next 3 months of liver regeneration after PH, the contribution of polyploidization to liver mass increase was negative because of depolyploidization of liver parenchyma cell population. At this time hypertrophy was the main process determining the liver mass increase.
Liver Regeneration
Parenchyma
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The liver has a great capacity to regenerate. Hepatocytes, the parenchymal cells of the liver, can regenerate in one of two ways: hepatocyte- or biliary-driven liver regeneration. In hepatocyte-driven liver regeneration, regenerating hepatocytes are derived from preexisting hepatocytes, whereas, in biliary-driven regeneration, regenerating hepatocytes are derived from biliary epithelial cells (BECs). For hepatocyte-driven liver regeneration, there are excellent rodent models that have significantly contributed to the current understanding of liver regeneration. However, no such rodent model exists for biliary-driven liver regeneration. We recently reported on a zebrafish liver injury model in which BECs extensively give rise to hepatocytes upon severe hepatocyte loss. In this model, hepatocytes are specifically ablated by a pharmacogenetic means. Here we present in detail the methods to ablate hepatocytes and to analyze the BEC-driven liver regeneration process. This hepatocyte-specific ablation model can be further used to discover the underlying molecular and cellular mechanisms of biliary-driven liver regeneration. Moreover, these methods can be applied to chemical screens to identify small molecules that augment or suppress liver regeneration.
Liver Regeneration
Liver cytology
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The liver has a great capacity to regenerate. Hepatocytes, the parenchymal cells of the liver, can regenerate in one of two ways: hepatocyte- or biliary-driven liver regeneration. In hepatocyte-driven liver regeneration, regenerating hepatocytes are derived from preexisting hepatocytes, whereas, in biliary-driven regeneration, regenerating hepatocytes are derived from biliary epithelial cells (BECs). For hepatocyte-driven liver regeneration, there are excellent rodent models that have significantly contributed to the current understanding of liver regeneration. However, no such rodent model exists for biliary-driven liver regeneration. We recently reported on a zebrafish liver injury model in which BECs extensively give rise to hepatocytes upon severe hepatocyte loss. In this model, hepatocytes are specifically ablated by a pharmacogenetic means. Here we present in detail the methods to ablate hepatocytes and to analyze the BEC-driven liver regeneration process. This hepatocyte-specific ablation model can be further used to discover the underlying molecular and cellular mechanisms of biliary-driven liver regeneration. Moreover, these methods can be applied to chemical screens to identify small molecules that augment or suppress liver regeneration.
Liver Regeneration
Liver cytology
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