Remarkable heterogeneity displayed by oval cells in rat and mouse models of stem cell–mediated liver regeneration

Jelnes, Peter; Santoni-Rugiu, Eric; Rasmussen, Morten; Friis, Susanne Lunøe; Nielsen, Jens Høiriis; Tygstrup, Niels; Bisgaard, Hanne Cathrine

doi:10.1002/hep.21569

Cited by 101 publications

(80 citation statements)

References 26 publications

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“…Higher alpha-fetoprotein (AFP) and delta-like protein expression in the proximal oval cells has already been described. 17,18 Similar zonal distribution could be demonstrated for the expression of other differentiation-related genes. Distal and proximal oval cell groups have been microdissected separately from frozen sections, and the relative gene expression has been analyzed by real-time quantitative RT-PCR.…”

Section: Resultssupporting

confidence: 61%

Structural analysis of oval-cell-mediated liver regeneration in rats

et al. 2012

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We have analyzed the architectural aspects of progenitor-cell-driven regenerative growth in rat liver by applying the 2-acetaminofluorene/partial hepatectomy experimental model. The regeneration is initiated by the proliferation of so-called oval cells. The oval cells at the proximal tips of the ductules have a more differentiated phenotype and higher proliferative rate. This preferential growth results in the formation of a seemingly random collection of small hepatocytes, called foci. These foci have no clonal origin, but possess a highly organized structure, which shows similarities to normal hepatic parenchyma. Therefore, they can easily remodel into the lobular structure. Eventually, the regenerated liver is constructed by enlarged hepatic lobules; no new lobules are formed during this process. The foci of the Solt-Farber experimental hepatocarcinogenesis model have identical morphological features; accordingly, they also represent only regenerative, not neoplastic, growth. Conclusion: Progenitor-cell-driven liver regeneration is a well-designed, highly organized tissue reaction, and better comprehension of the architectural events may help us to recognize this process and understand its role in physiological and pathological reactions. (HEPATOLOGY 2012;56:1457-1467 T here are several alternative mechanisms of liver regeneration. 1 Hepatocytes can enter the cell cycle or enlarge, and the consequent compensatory hyperplasia or hypertrophy replaces the lost liver mass. We have demonstrated that new hepatic lobules are not formed during this type of regeneration, but the remaining lobes grow exclusively by the enlargement of preexistent hepatic lobules. 2 If the hepatocytes are compromised, the progenitor cell compartment is activated and the liver regenerates by means of the socalled oval cells in the rat. 3 Oval cells invade the liver parenchyma from the periportal region. They form ductules, which are the extensions of the canals of Hering. 4 The distribution of the differentiating cells can be different, depending on the species and etiology. In human liver, singular intermediate hepatobiliary cells can often be observed in proliferating ductules after extensive necrosis, 5 but small groups of differentiating cells are also described in chronic hepatitis and cirrhosis. 6,7 The 2-acetaminofluorene/partial hepatectomy (AAF-PH) model 8 is one of the most widely applied experiments to study oval cell proliferation and differentiation in rats. We characterized the differentiating progenitor cells in this experimental model. Two alternative patterns of differentiation were observed previously depending on the applied dose of AAF. 9 In the case of a low dose (2.5 mg/kg/day of AAF), differentiation occurred earlier and practically all the oval cells transformed into small, newly formed hepatocytes. If the dose of AAF was higher (5 mg/kg/ day of AAF), differentiation occurred later and involved only a small portion of oval cells. Sharply

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Section: Resultssupporting

confidence: 61%

Structural analysis of oval-cell-mediated liver regeneration in rats

et al. 2012

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“…In support of this, a recent work has delineated the profound phenotypic heterogeneity displayed by oval cells in different rat and mouse models of oval cell-mediated liver regeneration. 48 It seems reasonable that the same diversity may apply to the regulatory mechanisms operating in these cells. Thus, mouse oval cells isolated from CDE-treated mouse livers express cytokines such as lymphotoxin-␤, interferon-␥, interleukin-6, 49,50 suggesting that they may respond both to autocrine and paracrine cytokine stimulation.…”

Section: Discussionmentioning

confidence: 99%

Deletion of the Met Tyrosine Kinase in Liver Progenitor Oval Cells Increases Sensitivity to Apoptosis in Vitro

Castillo

Factor

Fernández

et al. 2008

The American Journal of Pathology

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“…Hepatoblasts are considered a heterogeneous population with potential hierarchical organization and various degrees of differentiation (113). Therefore, many controversial issues including differentiation status and the repopulation capability of markerpositive hepatoblasts have been raised, even using robust stem cell markers (95,114,115).…”

Section: Shared Features Of Liver Development and Liver Cancer Develomentioning

confidence: 99%

Cancer stem cells in the development of liver cancer

Yamashita

Wang²

2013

J. Clin. Invest.

454

431

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Liver cancer is an aggressive disease with a poor outcome. Several hepatic stem/progenitor markers are useful for isolating a subset of liver cells with stem cell features, known as cancer stem cells (CSCs). These cells are responsible for tumor relapse, metastasis, and chemoresistance. Liver CSCs dictate a hierarchical organization that is shared in both organogenesis and tumorigenesis. An increased understanding of the molecular signaling events that regulate cellular hierarchy and stemness, and success in defining key CSC-specific genes, have opened up new avenues to accelerate the development of novel diagnostic and treatment strategies. This Review highlights recent advances in understanding the pathogenesis of liver CSCs and discusses unanswered questions about the concept of liver CSCs.

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Remarkable heterogeneity displayed by oval cells in rat and mouse models of stem cell–mediated liver regeneration

Cited by 101 publications

References 26 publications

Structural analysis of oval-cell-mediated liver regeneration in rats

Structural analysis of oval-cell-mediated liver regeneration in rats

Deletion of the Met Tyrosine Kinase in Liver Progenitor Oval Cells Increases Sensitivity to Apoptosis in Vitro

Cancer stem cells in the development of liver cancer

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