Hypertrophy and Unconventional Cell Division of Hepatocytes Underlie Liver Regeneration

Miyaoka, Yuichiro; Ebato, Kazuki; Kato, Hidenori; Arakawa, Satoko; Shimizu, Shigeomi; Miyajima, Atsushi

doi:10.1016/j.cub.2012.05.016

Cited by 398 publications

(422 citation statements)

References 36 publications

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“…Forced NICD2 expression in normal liver was achieved by the hydrodynamic gene delivery method as described 3. Briefly, an expression plasmid encoding Nicd2 complementary DNA or control empty vector21 was dissolved in TransIT‐EE Hydrodynamic Delivery Solution (Mirus Bio, Madison, WI) and injected through the tail vein.…”

Section: Methodsmentioning

confidence: 99%

“…Following partial hepatectomy, mature hepatocytes vigorously self‐proliferate and restore the lost volume and function 3. In contrast, in the case of severe liver fibrosis/cirrhosis when mature hepatocytes show minimal division, it is generally considered that hepatic progenitor cells (HPCs) are mobilized to proliferate and differentiate into mature hepatocytes 4, 5.…”

Section: Introductionmentioning

confidence: 99%

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Identification of a novel alpha‐fetoprotein‐expressing cell population induced by the Jagged1/Notch2 signal in murine fibrotic liver

Nakano

Nakao

Sumiyoshi

et al. 2017

Hepatology Communications

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The liver is well known to possess high regenerative capacity in response to partial resection or tissue injury. However, liver regeneration is often impaired in the case of advanced liver fibrosis/cirrhosis when mature hepatocytes can hardly self‐proliferate. Hepatic progenitor cells have been implicated as a source of hepatocytes in regeneration of the fibrotic liver. Although alpha‐fetoprotein (AFP) is known as a clinical marker of progenitor cell induction in injured/fibrotic adult liver, the origin and features of such AFP‐producing cells are not fully understood. Here, we demonstrate a unique and distinct AFP‐expressing cell population that is induced by the Jagged1/Notch2 signal in murine fibrotic liver. Following repeated carbon tetrachloride injections, a significant number of AFP‐positive cells with high proliferative ability were observed along the fibrous septa depending on the extent of liver fibrosis. These AFP‐positive cells exhibited features of immature hepatocytes that were stained positively for hepatocyte‐lineage markers, such as albumin and hepatocyte nuclear factor 4 alpha, and a stem/progenitor cell marker Sox9. A combination of immunohistological examination of fibrotic liver tissues and coculture experiments with primary hepatocytes and hepatic stellate cells indicated that increased Jagged1 expression in activated hepatic stellate cells stimulated Notch2 signaling and up‐regulated AFP expression in adjacent hepatocytes. The mobilization and proliferation of AFP‐positive cells in fibrotic liver were further enhanced after partial hepatectomy, which was significantly suppressed in Jagged1‐conditional knockout mice. Finally, forced expression of the intracellular domain of Notch2 in normal liver induced a small number of AFP‐expressing hepatocytes in vivo. Conclusion: Insight is provided into a novel pathophysiological role of Jagged1/Notch2 signaling in the induction of AFP‐positive cells in fibrotic liver through the interaction between hepatocytes and activated hepatic stellate cells. (Hepatology Communications 2017;1:215‐229)

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of a novel alpha‐fetoprotein‐expressing cell population induced by the Jagged1/Notch2 signal in murine fibrotic liver

Nakano

Nakao

Sumiyoshi

et al. 2017

Hepatology Communications

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“…In addition to LPCs, MHs compensate the loss of hepatocytes by proliferation and hypertrophy after acute liver injuries (12,13). Furthermore, MHs have been shown to convert to cholangiocyte-like cells both in vitro and in vivo (14 -16).…”

mentioning

confidence: 99%

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

Nishikawa

Ichinohe

et al. 2014

Journal of Biological Chemistry

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“…The combination of shear stress-activated pathways, extracellular matrix remodeling with release of matrix-bound growth factors, and a relative increase in supply of signaling molecules from the (portal) circulation, initiate the regenerative cascade [7,9]. Hypertrophy of hepatocytes in the remnant liver is a first and immediate event after PHx [8,10,11]. Within 30 min after PHx, intrahepatic levels of tumor necrosis factor alpha and interleukin-6 increase and signaling via their respective receptors causes activation of the transcription factors nuclear factor-kappa B and signal transducer and activator of transcription 3 (STAT3) [7,8].…”

Section: Molecular Events After Partial Hepatectomymentioning

confidence: 99%

The role of bile salts in liver regeneration

et al. 2016

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A growing body of evidence has demonstrated that bile salts are important for liver regeneration following partial hepatectomy. The relative bile salt overload after partial liver resection causes activation of bile salt receptors in non-parenchymal (viz. the plasma membrane receptor TGR5) and parenchymal (viz. the intracellular receptor FXR) cells in the liver, thus, providing signals to the regenerative process. Impaired bile salt signaling in mice with genetic deficiency of Tgr5 or Fxr results in delayed liver regeneration after partial hepatectomy, and is accompanied by mortality in case of Fxr knock-out mice. Conversely, compensatory liver re-growth in hepatectomized mice can be stimulated by feeding of bile salts or alisol B 23-acetate, a natural triterpenoid agonist of Fxr. A large number of animal studies underscore the importance of strict maintenance of bile salt homeostasis for proper progression of liver regeneration. Both ileal and hepatic Fxr play a key role in regulation of bile salt homeostasis and, thus, preventing hepatotoxicity caused by excessive levels of bile salts. They further contribute to liver regeneration by induction of mitogenic factors. Agents that target bile salt receptors hold promise as drugs to stimulate liver regeneration in selected patients.

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Hypertrophy and Unconventional Cell Division of Hepatocytes Underlie Liver Regeneration

Abstract: Our findings demonstrate the importance of hypertrophy and the unconventional cell division cycle of hepatocytes in regeneration, prompting a significant revision of the generally accepted model of liver regeneration.

Cited by 398 publications

References 36 publications

Identification of a novel alpha‐fetoprotein‐expressing cell population induced by the Jagged1/Notch2 signal in murine fibrotic liver

Identification of a novel alpha‐fetoprotein‐expressing cell population induced by the Jagged1/Notch2 signal in murine fibrotic liver

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

The role of bile salts in liver regeneration

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