Binucleated Human Hepatocytes: Endomitosis Mechanism Revealed

Core Concepts

The author explores how human hepatocytes undergo endomitosis, revealing the mechanism behind binucleation through loss of membrane anchorage to the midbody during late cytokinesis.

Abstract

The study investigates endomitosis in human hepatocytes using fetal-derived organoids. Cells in endomitosis lose membrane anchorage to the midbody during cytokinesis, leading to binucleation. WNT signaling inhibits binucleation, and E2F7/8 are crucial for promoting binucleation. The research provides insights into non-canonical cell cycles and polyploidization mechanisms in human liver cells.
Key Points:

Endoreplication and endomitosis lead to polyploidy in mammalian tissues.
Human hepatocytes transition from canonical to non-canonical cell cycles.
Binucleated cells arise due to loss of membrane anchorage during cytokinesis.
WNT signaling inhibits binucleation, while E2F7/8 promote it.
Liver polyploidization is essential for tissue function and regeneration.

Stats

In a healthy liver, less than 0.01% of hepatocytes are actively cycling.
Upon injury, hepatocytes can proliferate and regrow the organ.
Polyploid mouse livers contain around 80% binucleated cells.
Adult human livers consist of up to 20% binucleated cells.

Quotes

"Cells undergoing endomitosis inhibit cell division by losing membrane anchorage to the midbody."
"WNT signaling supports proliferation and inhibits binucleation of human hepatocytes."
"E2F7 and E2F8 control hepatocyte differentiation and binucleation."

Key Insights Distilled From

Binucleated human hepatocytes arise through loss of membrane anchorage to the midbody during endomitosis

by Darmasaputra... at www.biorxiv.org 04-13-2023

https://www.biorxiv.org/content/10.1101/2023.04.13.536716v1

Deeper Inquiries

What implications do these findings have for understanding liver regeneration beyond the scope of this study

The findings of this study on human hepatocytes undergoing endomitosis have significant implications for understanding liver regeneration beyond the scope of the research. One key implication is related to the role of WNT signaling and E2F7/8 in regulating non-canonical cell cycles, specifically endomitosis, in hepatocytes. Understanding how these pathways control binucleation can provide insights into liver development and regeneration processes. By elucidating the molecular mechanisms that drive endomitosis and lead to polyploidization in hepatocytes, researchers can gain a better understanding of how liver tissue maintains homeostasis and responds to injury.
Moreover, since polyploid cells play essential roles in tissue growth, metabolism, and response to genotoxic stress, further exploration of these pathways could uncover novel targets for therapeutic interventions aimed at enhancing liver regeneration or treating liver diseases. The ability to modulate non-canonical cell cycles through WNT signaling or E2F7/8 activity may hold promise for developing strategies to promote efficient liver regeneration following injury or disease.

Could there be alternative explanations for the inhibition of cytokinesis in endomitotic cells

While the inhibition of cytokinesis in endomitotic cells observed in this study was attributed to loss of membrane anchorage proteins like RacGAP1, Anillin, and CIT-K during late cytokinesis stages leading to furrow regression, there could be alternative explanations for this phenomenon. One possible explanation could involve alterations in actin dynamics or defects in ESCRT-III machinery function at the midbody region.
For instance, changes in actin polymerization dynamics within the cleavage furrow might disrupt proper contractile ring formation or stability during late cytokinesis stages. Additionally, abnormalities in ESCRT-III complex components responsible for membrane abscission could impact normal completion of cytokinesis by failing to mediate plasma membrane scission between daughter cells effectively.
Further investigations focusing on actin cytoskeleton organization or ESCRT-mediated events during endomitosis M phase could provide additional insights into alternative mechanisms underlying cytokinetic inhibition observed in human hepatocytes undergoing endomitosis.

How might studying non-canonical cell cycles in human hepatocytes contribute to cancer research or therapeutic interventions

Studying non-canonical cell cycles such as endoreplication and endomitosis in human hepatocytes has important implications for cancer research and potential therapeutic interventions targeting tumor growth and progression. Understanding how these unique cell cycle modes are regulated can shed light on similar processes occurring within cancer cells that contribute to tumor heterogeneity and treatment resistance.
By unraveling the molecular pathways involved in controlling non-canonical cell cycles like those seen during hepatic polyploidization (e.g., WNT signaling pathway activation), researchers may identify new targets for anticancer therapies aimed at disrupting aberrant proliferation mechanisms characteristic of cancer cells. For example:

Targeted Therapies: Drugs that modulate WNT signaling components implicated in promoting binucleation (similarly found crucial for tumorigenesis) could be explored as targeted therapies against certain types of cancers where dysregulated polyploidy contributes significantly.

Cell Cycle Regulation: Insights into E2F7/8 functions related to inducing binucleation might offer opportunities for designing treatments that selectively inhibit abnormal mitotic processes prevalent among cancerous cells while sparing normal tissues.

Drug Resistance Mechanisms: Studying non-canonical cell cycles' involvement with drug resistance phenomena common among tumors can guide efforts towards overcoming therapy resistance by manipulating specific regulators identified from such studies.

Overall, investigating non-canonical cell cycle regulation provides a valuable framework not only for understanding fundamental biological processes but also potentially unlocking innovative approaches towards combating cancer through tailored interventions based on mechanistic insights gained from studying hepatic polyploidization dynamics.