Events
Paula Heinke: Dynamics of cell renewal in the human liver
Paula Heinke, from Olaf Bergmann Group, will defend her PhD thesis
Dynamics of cell renewal in the human liver
The liver is widely known for its extraordinary renewal capacity and represents therefore a good model for the study of cellular regeneration. The replacement of hepatic tissue relies mainly on the proliferation of the parenchymal hepatocytes. Studies of the past century established their physiological life span in animal models but the commonly used techniques to characterize cellular turnover could not be applied to humans due to methodological restrictions. It is debatable how the findings from animal studies translate to a human life span, considering the different life expectations and variations in liver cell biology. Therefore, there is only limited knowledge to what degree the exchange of liver cells and in particular hepatocytes is necessary for humans to preserve the physiological functions and pronounced metabolic activity of the organ. A detailed characterization of the dynamics of human hepatocyte turnover, their cellular age distribution, and the consequences for cellular function in the aging liver is missing so far.
In the present study, we used retrospective 14C birth dating to quantify the physiological liver cell turnover in humans. This method utilizes the incorporation of nuclear-bomb-test-derived 14C into biological material. The quantification of 14C in genomic DNA enables the determination of cellular ages as shown successfully in several human organs. We established the technique for the analysis of human liver samples and measured genomic 14C levels in unsorted liver cells, hepatocytes, and nonhepatocytes. The 14C concentrations suggest that liver cells show a high turnover up to old age and that they are steadily replaced over the whole human life span.
As hepatocytes constitute a heterogeneous population with a continuous increase in ploidy level in the aging organ, we asked whether this would be reflected in the genomic 14C concentrations. We used hepatocyte nuclei and primary hepatocytes to separate hepatocyte populations of different nuclear and cellular ploidy levels, respectively. The comparison of paired measurements from the same subjects showed that both nuclear and cellular polyploid hepatocyte fractions have significantly higher 14C levels than the respective diploids. This suggests that hepatocytes also have a differential turnover behavior depending on their ploidy level.
To characterize the hepatocyte replacement in more detail, we developed a mathematical model which estimates cellular turnover rates from our 14C measurements. This model reflects essential parameters of life-long hepatocyte biology and includes our observations of the age- dependent development of the total DNA contents and ploidy distribution of hepatocytes. We report that hepatocyte turnover does indeed highly depend on the ploidy level. As already
indicated from our initial analysis of the 14C data, we find very constant turnover rates which change only slightly during adulthood. At a medium age, the annual birth rate of mononucleated diploid hepatocytes accounts for 71 %, while only 10 % of binucleated diploid and 1 % of mononucleated tetraploid cells undergo cell division. This suggests that almost 700 million hepatocytes are born every day. Accordingly, we estimate that diploid hepatocytes are on average 0.7 years old, while cells of both higher ploidy levels are longer-lived and have an average age of 4.4 years.
Although the cellular turnover rates and ages are relatively constant during human adulthood, we observe tremendous changes in the overall age distribution in the liver. This results from the continuous growth of the polyploid compartment. At a young age, the liver is mainly populated by diploid hepatocytes with most hepatocytes being replaced within one year. In contrast, the aged organ comprises more than 40 % polyploid hepatocytes, which can reside in the liver for up to a decade. Nevertheless, the liver remains a young organ with an average age of fewer than three years during the complete lifetime.
Moreover, we used mathematical modeling to quantify the transitions between cell populations with different ploidy levels. The ploidy conveyor concept describes the continuous increase and decrease of hepatocyte ploidy. We report that such events are rare in humans. Both diploid and polyploid cells are mainly replenished by cell divisions within their ploidy class. Furthermore, we observe that if a stem cell population existed in the liver its contribution to the hepatocyte pool would be very small under homeostatic conditions.
Altogether, we present an integrated model of the physiological liver cell replacement in humans. It shows that hepatic tissue renewal mainly depends on the diploid hepatocytes, while polyploid cells are restricted in their turnover capacity. The increase of the ploidy level in the aging organ could act as a resilience factor but also be an aspect of impaired renewal in the progression of age-related liver diseases.