TGFbeta Induces Binucleation/Polyploidization in Hepatocytes through a Src-Dependent Cytokinesis Failure.

Area of Science:

• Hepatology
• Cell Biology
• Molecular Biology

Background:

• Adult mammalian livers contain both binucleated and mononucleated polyploid hepatocytes.
• Hepatic polyploidization begins postnatally via hepatocyte binucleation, creating diverse ploidy classes.
• The functional roles of hepatocyte polyploidy are increasingly understood, but its triggers and maintenance mechanisms require further elucidation.

Purpose of the Study:

• To identify a key inducer of hepatocyte binucleation and polyploidization.
• To investigate the cellular and molecular mechanisms underlying TGFβ1-induced binucleation.

Main Methods:

• Hepatocytes were cultured and treated with various cytokines, including TGFβ1.
• Pharmacological inhibition of TGFβ signaling was performed in healthy mice during the weaning period.
• Video microscopy assessed cytokinesis, and molecular inhibitors identified signaling pathways involved.
• TGFβ withdrawal was used to observe the maintenance of the polyploid state.

Main Results:

• Transforming growth factor beta 1 (TGFβ1) induced binucleation in cultured hepatocytes.
• In vivo, inhibiting TGFβ signaling significantly reduced hepatocyte binucleation rates during weaning without affecting proliferation or liver index.
• TGFβ1-induced binucleation resulted from cytokinesis failure, characterized by RhoA-GTPase delocalization from the mid-body.
• The process was identified as Src-dependent, and TGFβ withdrawal allowed polyploid cells to maintain their state.

Conclusions:

• TGFβ1 is identified as a major inducer of hepatocyte binucleation in vitro and in vivo.
• Hepatocyte binucleation is mediated by TGFβ1-induced cytokinesis failure, regulated by the TGFβ/Src/RhoA molecular axis.
• This study reveals a novel role for TGFβ1 in regulating hepatic polyploidization through cytokinesis control.