The size of organs and tissues is basically determined by the number and size of their cells. However, little attention has been paid to this fundamental concept. The liver has a remarkable ability to regenerate after surgical resection (partial hepatectomy [PHx]), and hepatocytes account for about 80% of liver weight, so we investigate how the number and size of hepatocytes contribute to liver regeneration in mice. It has been generally accepted that hepatocytes undergo one or two rounds of cell division after 70% PHx. However, ploidy of hepatocytes is known to increase during regeneration, suggesting an unconventional cell cycle. We therefore examine cell cycle of hepatocytes in detail.

By developing a method for genetic fate mapping and a high-throughput imaging system of individual hepatocytes, we show that cellular hypertrophy makes the first contribution to liver regeneration; i.e., regeneration after 30% PHx is achieved solely by hypertrophy without cell division, and hypertrophy precedes proliferation after 70% PHx. Proliferation and hypertrophy almost equally contribute to regeneration after 70% PHx. Furthermore, although most hepatocytes enter cell cycle after 70% PHx, not all hepatocytes undergo cell division. In addition, binuclear hepatocytes undergo reductive divisions to generate two mononuclear daughter hepatocytes in some cases.

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.