The origins and functions of hepatic polyploidy

Zhang, Shuyuan; Lin, Yu Hsuan; Tarlow, Branden D.; Zhu, Min

doi:10.1080/15384101.2019.1618123

Cited by 35 publications

(31 citation statements)

References 119 publications

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“…DNA duplication occurs by alterations to the normal cell cycle through either mitotic slippage, endocycling (also termed endoreduplication or endoreplication), or endomitosis (cytokinesis failure) ( 105 , 107 – 109 ). Mitotic slippage is a semicomplete cell cycle in which the cell fails to resolve the mitotic spindle assembly checkpoint and, after a delay, exits a prolonged mitosis with a 4N nucleus ( 110 ). Endocycling encompasses alternating gap and S-phases that can result in polyploid cells of varying ploidy, up to 1,000 copies of the genome ( 111 ).…”

Section: Cancer Cells Access Evolutionary and Developmental Polyploidmentioning

confidence: 99%

Cancer recurrence and lethality are enabled by enhanced survival and reversible cell cycle arrest of polyaneuploid cells

Pienta¹,

Hammarlund

Brown

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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We present a unifying theory to explain cancer recurrence, therapeutic resistance, and lethality. The basis of this theory is the formation of simultaneously polyploid and aneuploid cancer cells, polyaneuploid cancer cells (PACCs), that avoid the toxic effects of systemic therapy by entering a state of cell cycle arrest. The theory is independent of which of the classically associated oncogenic mutations have already occurred. PACCs have been generally disregarded as senescent or dying cells. Our theory states that therapeutic resistance is driven by PACC formation that is enabled by accessing a polyploid program that allows an aneuploid cancer cell to double its genomic content, followed by entry into a nondividing cell state to protect DNA integrity and ensure cell survival. Upon removal of stress, e.g., chemotherapy, PACCs undergo depolyploidization and generate resistant progeny that make up the bulk of cancer cells within a tumor.

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Section: Cancer Cells Access Evolutionary and Developmental Polyploidmentioning

confidence: 99%

Cancer recurrence and lethality are enabled by enhanced survival and reversible cell cycle arrest of polyaneuploid cells

Pienta¹,

Hammarlund

Brown

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…This suggests a link between the onset of dietary intake and profound changes of hormonal (ie, insulin) production and liver polyploidization. 83 , 84 Indeed, insulin/phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) signaling has been found to be critical for the genesis of binucleated hepatocytes. 85 , 86 Destruction of insulin-producing rat pancreatic beta cells by streptozotocin before weaning reduced circulating levels of insulin and reduced the number of polyploid hepatocytes.…”

Section: Controversies Surrounding Hepatic Stem Cells and Their Rolesmentioning

confidence: 99%

Controversies Surrounding the Origin of Hepatocytes in Adult Livers and the in Vitro Generation or Propagation of Hepatocytes

Pek¹,

Liu²,

Nichane

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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This review discusses controversies regarding hepatic stem cells and their roles in liver maintenance and regeneration. Insights in liver regeneration helped advance in vitro studies to propagate primary hepatocytes and to generate hepatocytes from pluripotent stem cells. Epithelial cells in the liver (known as hepatocytes) are high-performance engines of myriad metabolic functions and versatile responders to liver injury. As hepatocytes metabolize amino acids, alcohol, drugs, and other substrates, they produce and are exposed to a milieu of toxins and harmful byproducts that can damage themselves. In the healthy liver, hepatocytes generally divide slowly. However, after liver injury, hepatocytes can ramp up proliferation to regenerate the liver. Yet, on extensive injury, regeneration falters, and liver failure ensues. It is therefore critical to understand the mechanisms underlying liver regeneration and, in particular, which liver cells are mobilized during liver maintenance and repair. Controversies continue to surround the very existence of hepatic stem cells and, if they exist, their spatial location, multipotency, degree of contribution to regeneration, ploidy, and susceptibility to tumorigenesis. This review discusses these controversies. Finally, we highlight how insights into hepatocyte regeneration and biology in vivo can inform in vitro studies to propagate primary hepatocytes with signals in liver regeneration and to generate hepatocytes de novo from pluripotent stem cells.

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“…Like cardiomyocytes, hepatocytes also exhibit species-specific differences in ploidy and nuclear number. Several reviews explore hepatocyte polyploidy in depth (Gentric and Desdouets 2014 ; Zhang et al 2019 ). Hepatocyte polyploidy and multinucleation varies between species.…”

Section: Distinct Architecture: a Survey Of Tissues With Extra Genomementioning

confidence: 99%

Communal living: the role of polyploidy and syncytia in tissue biology

Peterson

Fox

2021

Chromosome Res

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Multicellular organisms are composed of tissues with diverse cell sizes. Whether a tissue primarily consists of numerous, small cells as opposed to fewer, large cells can impact tissue development and function. The addition of nuclear genome copies within a common cytoplasm is a recurring strategy to manipulate cellular size within a tissue. Cells with more than two genomes can exist transiently, such as in developing germlines or embryos, or can be part of mature somatic tissues. Such nuclear collectives span multiple levels of organization, from mononuclear or binuclear polyploid cells to highly multinucleate structures known as syncytia. Here, we review the diversity of polyploid and syncytial tissues found throughout nature. We summarize current literature concerning tissue construction through syncytia and/or polyploidy and speculate why one or both strategies are advantageous.

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The origins and functions of hepatic polyploidy

Cited by 35 publications

References 119 publications

Cancer recurrence and lethality are enabled by enhanced survival and reversible cell cycle arrest of polyaneuploid cells

Cancer recurrence and lethality are enabled by enhanced survival and reversible cell cycle arrest of polyaneuploid cells

Controversies Surrounding the Origin of Hepatocytes in Adult Livers and the in Vitro Generation or Propagation of Hepatocytes

Communal living: the role of polyploidy and syncytia in tissue biology

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