Zonal Distribution of Cell Proliferation in the Liver of Untreated B6C3F1 and C57BL Mice

Abstract

To determine the lobular distribution of hepatocellular proliferation, S-phase response was measured in untreated adult male B6C3F1 and C57BL mice at ages 11, 14, and 23 weeks. The percentage of cells in S-phase (labeling index, LI) was evaluated using immunohistochemical detection of 5-bromo-2 -deoxyuridine (BrdU). The BrdU was delivered either by a single ip injection 2 hr prior to sacrifice or via an osmotic minipump implanted subcutaneously for 3 or 7 days. Mitotic and apoptotic indices were determined on H&E stained sections. Animals of both strains and all ages revealed highest LI in the intermediate compartment of the liver acinus (zone 2) irrespective of the length of BrdU application. Cell proliferation in this zone was at all time points significantly higher than elsewhere in the liver. The mitotic index confirmed the data obtained by the S-phase response study. Apoptosis was rarely observed. With regard to rodent data in chemical carcinogenesis and the way they should be evaluated, this study proved that the acinar distribution of proliferating cells in liver of mice is different from that in rats, since, according to the literature, rats reveal highest cell proliferative activity in the periportal zone.

Prenatal exposure of mice to the human liver carcinogen aflatoxin B1 reveals a critical window of susceptibility to genetic change

“…Zonal differences in cell proliferation in the liver occur during fetal development, postnatal growth and homeostasis in the adult organ. 37–38 If tissue progenitor cells are at greater risk of mutation during fetal development, mutant cells emerging from these populations would be expected to increase the MF in the tissue, which could account for the observed increase in MF at the ten-week time point.…”

DNA Synthesis in Periportal and Perivenous Hepatocytes of Intact and Hepatectomized Young Mice

“…[24,25] Specific spatial patterns of hepatocyte replication were reported for rodent liver. [11,14,26] A heterogeneous distribution of DNAs in the liver of hepatectomized rats with the highest proliferative rate in periportal hepatocytes was demonstrated. [7,14] In agreement with this, we found that values of DNAs in the PPH of hepatectomized livers were statistically different from those in the PVH at 42 and 46 hr PH, with the highest values in PPH ( Table 2).…”

“…[10] Administration of bromodeoxyuridine (BrdU) is used to determine the S-phase response in cell proliferation studies. [11] In addition, studies performed in adult normal liver have found that S-phase hepatocytes are localized at all segments of the lobule, [12] and that their turnover occurs randomly throughout the lobule. [13] However, other reports have indicated that the hepatocytes subpopulation in rat regenerating livers, synthesizes DNA with a heterogeneous distribution, and that cell proliferation is highest in the periportal area and decreases toward the draining vein.…”

“…[13] However, other reports have indicated that the hepatocytes subpopulation in rat regenerating livers, synthesizes DNA with a heterogeneous distribution, and that cell proliferation is highest in the periportal area and decreases toward the draining vein. [7,11,14] The aim of this study was to analyze the magnitude and distribution of DNA synthesis hepatocytes within the lobule of intact and hepatectomized young mice liver along a circadian period. For this purpose, we compare DNAs values between periportal and perivenous hepatocytes, in intact livers over a circadian period and during liver regeneration, at different post-hepatectomy times.…”

Mechanism of action of liver growth induced by peroxisome proliferators

“…The fact that the zonal distribution of DNA synthesis in the rat liver is known (Barrass et al, 1993) and that Barrass has established a reliable method to study this, gave reason to make similar studies on mouse liver, as there are no directly comparable data in mice (Burkhardt et al, 2004). …”