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J. Biol. Chem., Vol. 278, Issue 21, 19095-19101, May 23, 2003

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Liver Cell Polyploidization: A Pivotal Role for Binuclear Hepatocytes^*,

Jacques-Emmanuel Guidotti  , Olivier Brégerie  , Aude Robert , Pascale Debey ¶, Christian Brechot  and Chantal Desdouets  ||

From the INSERM U370, CHU Necker, 156 Rue de Vaugirard, 75015 Paris, France, ^¶ Unité Mixte de Recherche 8646 CNRS-MNHN, U565 INSERM, Muséum National d'Histoire Naturelle, 53 Rue Buffon, 75005 Paris, France

Polyploidy is a general physiological process indicative of terminal differentiation. During liver growth, this process generates the appearance of tetraploid (4n) and octoploid (8n) hepatocytes with one or two nuclei. The onset of polyploidy in the liver has been recognized for quite some time; however, the cellular mechanisms that govern it remain unknown. In this report, we observed the sequential appearance during liver growth of binuclear diploid (2 x 2n) and mononuclear 4n hepatocytes from a diploid hepatocyte population. To identify the cell cycle modifications involved in hepatocyte polyploidization, mitosis was then monitored in primary cultures of rat hepatocytes. Twenty percent of mononuclear 2n hepatocytes failed to undergo cytokinesis with no observable contractile movement of the ring. This process led to the formation of binuclear 2 x 2n hepatocytes. This tetraploid condition following cleavage failure did not activate the p53-dependent checkpoint in G₁. In fact, binuclear hepatocytes were able to proceed through S phase, and the formation of a bipolar spindle during mitosis constituted the key step leading to the genesis of two mononuclear 4n hepatocytes. Finally, we studied the duplication and clustering of centrosomes in the binuclear hepatocyte. These cells exhibited two centrosomes in G₁ that were duplicated during S phase and then clustered by pairs at opposite poles of the cell during metaphase. This event led only to mononuclear 4n progeny and maintained the tetraploidy status of hepatocytes.

Received for publication, January 29, 2003 , and in revised form, March 6, 2003.

^|| To whom correspondence should be addressed. Tel.: 33-1-40615545; Fax: 33-1-40-615581; E-mail: desdouet{at}necker.fr.

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