Abstract
Partial hepatectomy (PH) triggers hepatocyte proliferation–mediated liver repair and is widely used to study the mechanisms governing liver regeneration in mice. However, the dynamics of the hepatocyte proliferative response to PH remain unclear. We found that PH-induced mouse liver regrowth was driven by four consecutive waves of hepatocyte replication. The first wave exhibited the highest magnitude followed by two moderate waves and one minor wave. Underlying this continuous hepatocyte replication was persistent activation of cell cycle components throughout the period of liver regeneration. Hepatocyte mitotic activity in the first three proliferative cycles showed a circadian rhythm manifested by three corresponding mitosis peaks, which were always observed at Zeitgeber time 0. The Bmal1-Clock/Wee1/Cdc2 pathway has been proposed by others to govern the circadian rhythm of hepatocyte mitosis during liver regeneration. However, we did not observe the correlations in the expression or phosphorylation of these proteins in regenerating livers. Notably, Bmal1 protein displayed frequent changes in hepatic distribution and cellular localization as the liver regrowth progressed. Further, three waves of hepatic fat accumulation occurred during hepatic regeneration. The first started before and lasted through the first round of hepatocyte proliferation, whereas the second and third occurred concomitantly with the second and third mitotic peaks, respectively.ConclusionPH-induced liver regeneration consists of four continuous waves of hepatocyte proliferation coupled with three waves of hepatic fat accumulation. Bmal1, Wee1, and Cdc2 may not form a pathway regulating the circadian rhythm of hepatocyte mitosis during liver regeneration.
Highlights
The liver is innately able to regenerate in response to its mass loss caused by a variety of injuries
partial hepatectomy (PH)-induced liver regeneration consists of four continuous waves of hepatocyte proliferation coupled with three waves of hepatic fat accumulation
PH-induced liver regeneration consists of four consecutive waves of hepatocyte proliferation
Summary
The liver is innately able to regenerate in response to its mass loss caused by a variety of injuries. The initiation, expansion, and termination of the regenerative response are composed of numerous highly coordinated biological events that occur simultaneously or sequentially at the molecular, cellular, and tissue levels [1,2,3]. Central to these events is mature adult hepatocyte proliferation, as the first line of regenerative response to acute or early chronic liver injury [4,5]. The initiation responses, including the production of priming factors (e.g., IL-6 and TNFa), are thought to prime hepatocytes to respond to growth factors (e.g., HGF and EGF) [5]. Understanding the regulation of hepatocyte replication is of paramount importance in developing clinical approaches toward liver repair
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