The liver performs multiple functions essential for the maintenance of homeostasis. It not only plays a central role in the metabolism, synthesis, and storage of nutrients, but also is the main detoxifying organ of the body. The function of liver is mainly dependent on hepatocytes which constitute 78% of liver volume and 70% of all liver cells. After weaning, about 40% dividing hepatocytes undergo polyploidization gradually, which has been thought to be a result of failed cytokinesis with no contractile ring formation (also called cytokinesis failure). In addition to failed cytokinesis, polyploidy can be caused by several modified cell-division cycles. Therefore, we hypothesize that a different type of cytokinesis may exist for processing heterogeneous DNA content of hepatocyte in liver. With the time-lapse recording, a novel cell dividing type, abscission failure, was observed at the final step of cytokinesis in primary cultured hepatocytes. It is consistent with previous study that around 35% hepatocytes exhibit failed cytokinesis without contractile ring formation in our system. Interestingly, our preliminary data also indicated that around 5% hepatocytes perform abscission failure from over 500 dividing cells and turn into polyploidy. Polyploidization of hepatocyte is considered to indicate the termination of differentiation during development in young mice. In adults, polyploidization is caused by senescence or cellular stress such as surgical resection, toxic exposure, or viral infections. Moreover, pathological polyploidy has been shown positive correlation with hepatocellular carcinoma (HCC). In this regards, the major aim of this proposal is to address the underlying mechanism and influence of abscission failure on the physiological functions and pathological progression of hepatocyte in liver. Specific aims are: 1. We have employed the time-lapse recording to demonstrate that 5% hepatocytes perform abscission failure at the final step of cytokinesis. We will further characterize whether abscission failure occurs through out the lifespan or just happens within a specific time window. And the spatial distribution in the lobule of liver will be evaluated. 2. Based on the data from aim 1, we will next address the physiological function of abscission failure in liver. 3. Because polyploidization changes genomic profile and companies with senescence and tumorigenesis, to investigate the relationship between abscission failure of hepatocyte and liver pathological progressing will be our next step. 4. We will elucidate the underlying mechanism of abscission failure in liver.
|Effective start/end date||8/1/17 → 7/31/18|