Sry HMG Box Protein 9-positive (Sox9+) Epithelial Cell Adhesion Molecule-negative (EpCAM−) Biphenotypic Cells Derived from Hepatocytes Are Involved in Mouse Liver Regeneration

Tanimizu, Naoki; Nishikawa, Yuji; Ichinohe, Norihisa; Akiyama, Haruhiko; Mitaka, Toshihiro

doi:10.1074/jbc.m113.517243

Cited by 96 publications

(92 citation statements)

References 35 publications

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“…When cultured cells were exposed to hepatocyte-differentiation medium containing dexamethasone and oncostatin-M, hepPDs showed an enhanced ability to upregulate albumin mRNA (Fig 4F) compared with Rspo-1 containing expansion medium. The ability of hepatocyte-derived progenitors to reactivate hepatocyte gene expression in vitro is in agreement with a recent publication(Tanimizu et al, 2014). …”

Section: Resultssupporting

confidence: 91%

“…On the contrary, good evidence now exists that hepatocytes can “transdifferentiate” into ductal biliary epithelial cells in certain injury models(Michalopoulos et al, 2005; Sekiya and Suzuki, 2014; Tanimizu et al, 2014; Yanger et al, 2013) and/or by forced genetic modulation of the developmentally important Notch (Jeliazkova et al, 2013; Yanger et al, 2013) and Hippo pathways(Yimlamai et al, 2014). In the context of cancer, multiple groups have shown that hepatocytes can be transformed into a biliary-cell-like tumor, cholangiocarcinoma, previously thought to originate exclusively from cholangiocytes(Fan et al, 2012; Sekiya and Suzuki, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…The observation that “dedifferentiated” or “mesenchymal” hepatocytes are primed to reacquire hepatic functions in vitro (Chen et al, 2012; Dunn et al, 1989; Santangelo et al, 2011; Tanimizu et al, 2014) raised the question whether hepatocyte-derived progenitors could differentiate back to hepatocytes in vivo . Here we characterized hepatocyte-derived progenitors cells in a mouse model of oval cell activation.…”

Section: Introductionmentioning

confidence: 99%

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Bipotential Adult Liver Progenitors Are Derived from Chronically Injured Mature Hepatocytes

Tarlow¹,

Pelz²,

Naugler³

et al. 2014

Cell Stem Cell

464

465

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Summary Adult liver progenitor cells are biliary-like epithelial cells that emerge only under injury conditions in the periportal region of the liver. They exhibit phenotypes of both hepatocytes and bile ducts. However, their origin and their significance to injury repair remain unclear. Here, we used a chimeric lineage tracing system to demonstrate that hepatocytes contribute to the progenitor pool. RNA-sequencing, ultrastructural analysis, and in vitro progenitor assays revealed that hepatocyte-derived progenitors were distinct from their biliary-derived counterparts. In vivo lineage tracing and serial transplantation assays showed that hepatocyte-derived proliferative ducts retained a memory of their origin and differentiated back into hepatocytes upon cessation of injury. Similarly, human hepatocytes in chimeric mice also gave rise to biliary progenitors in vivo. We conclude that human and mouse hepatocytes can undergo reversible ductal metaplasia in response to injury, expand as ducts and subsequently contribute to restoration of the hepatocyte mass.

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Section: Resultssupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Bipotential Adult Liver Progenitors Are Derived from Chronically Injured Mature Hepatocytes

Tarlow¹,

Pelz²,

Naugler³

et al. 2014

Cell Stem Cell

464

465

View full text Add to dashboard Cite

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“…27 Recent studies using genetic lineage-tracing techniques in transgenic mice have challenged the contribution of HPC/OCs to liver regeneration. 28,29 Nevertheless, HPC/OC activation is often associated with myofibroblast cell activation and liver fibrosis during chronic liver disease. 30–32 In human studies, HPC/OCs accumulate as injuries become more severe, indicating HPC proliferation increases with progressively worsening liver injury and fibrosis.…”

Section: Hpc/oc Characteristics and Originsmentioning

confidence: 99%

Hepatic progenitor cell activation in liver repair

et al. 2017

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The liver possesses an extraordinary ability to regenerate after injury. Hepatocyte-driven liver regeneration is the default pathway in response to mild-to-moderate acute liver damage. When replication of mature hepatocytes is blocked, facultative hepatic progenitor cells (HPCs), also referred to as oval cells (OCs) in rodents, are activated. HPC/OCs have the ability to proliferate clonogenically and differentiate into several lineages including hepatocytes and bile ductal epithelia. This is a conserved liver injury response that has been studied in many species ranging from mammals (rat, mouse, and human) to fish. In addition, improper HPC/OC activation is closely associated with fibrotic responses, characterized by myofibroblast activation and extracellular matrix production, in many chronic liver diseases. Matrix remodeling and metalloprotease activities play an important role in the regulation of HPC/OC proliferation and fibrosis progression. Thus, understanding molecular mechanisms underlying HPC/OC activation has therapeutic implications for rational design of anti-fibrotic therapies.

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“…Furthermore, adult hepatocytes exhibit significant plasticity in vivo, a phenomenon that may give the appearance of stem-cell-mediated differentiation (Michalopoulos et al, 2005; Tanimizu et al, 2014; Yanger et al, 2013). In order to obtain direct evidence for liver stem cell activity in vivo, we labeled three distinctive cell populations in the liver—BECs, hepatocytes, and rapidly dividing cells—using both direct genetic and unbiased nucleoside analog-based lineage labeling tools under multiple ADC-inducing injury conditions.…”

Section: Introductionmentioning

confidence: 99%

Adult Hepatocytes Are Generated by Self-Duplication Rather than Stem Cell Differentiation

et al. 2014

Self Cite

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SUMMARY The liver is thought to utilize facultative stem cells, also known as “oval cells” or “atypical ductal cells” (ADCs), for regeneration following various types of injury. However, this notion has been based largely on in vitro studies and transplantation models; where lineage tracing has been used, results have been conflicting and effect sizes have been small. Here, we used genetic and nucleoside analog-based tools to mark and track the origin and contribution of various cell populations to liver regeneration in vivo following several ADC-inducing insults. We report that, contrary to prevailing stem-cell-based models of regeneration, virtually all new hepatocytes come from preexisting hepatocytes.

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Sry HMG Box Protein 9-positive (Sox9+) Epithelial Cell Adhesion Molecule-negative (EpCAM−) Biphenotypic Cells Derived from Hepatocytes Are Involved in Mouse Liver Regeneration

Cited by 96 publications

References 35 publications

Bipotential Adult Liver Progenitors Are Derived from Chronically Injured Mature Hepatocytes

Bipotential Adult Liver Progenitors Are Derived from Chronically Injured Mature Hepatocytes

Hepatic progenitor cell activation in liver repair

Adult Hepatocytes Are Generated by Self-Duplication Rather than Stem Cell Differentiation

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