Liver biopsies from human females contain male hepatocytes in the absence of transplantation

Abstract

Fetal cells derived from pregnancy can persist in a woman's blood and tissues for decades and have been implicated in the pathogenesis of autoimmune disease. Transplantation studies based on donor sex mismatch suggest that circulating stem cells can lead to liver regeneration with donor-derived hepatocytes. However, male cells in female liver could derive from pregnancy. We investigated male cells in liver biopsies from women with sons and asked whether they were hematopoietic cells or hepatocytes. Fluorescence in situ hybridization for X-and Y-chromosomes with concomitant immunohistochemistry was employed to study 28 female liver biopsies: 14 with the autoimmune disease primary biliary cirrhosis (PBC), eight with Hepatitis C, and six with other diseases. Total male cells and those expressing hematopoietic (CD45) or hepatocyte (CAM-5.2) markers were quantified. None of the male cells were hematopoietic in origin, as shown by lack of CD45 expression. Instead, male cells with hepatocyte morphology expressing the hepatocyte marker CAM 5.2 were found in 25% of all biopsies (36% of PBC and 14% of others). Overall, male cells were found in 36% of female liver biopsies. Of the PBC livers 43% had male cells compared to 25% of Hepatitis C biopsies and 33% of others. There was a trend toward increased numbers of male cells in PBC compared to others (mean 1 per 30 000 host cells vs 0.17 in Hepatitis C and 0.35 in others). Thus, male cells found in livers of women with sons include cells that express hepatocyte antigens. Therefore, transplantation and stem cell differentiation studies using sex difference to conclude that donor cells regenerate liver may be confounded by fetal microchimerism. Whether fetal cells play a role in autoimmune diseases like PBC merits further investigation.

Protein Microarrays and Midtrimester Amniotic Fluids: A Novel Approach for the Diagnosis of Early Intrauterine Inflammation Related to Preterm Delivery

“…Differences in antibody levels between PTD and TD women have been observed also for the IgG against the other VTP assessed, but such differences never reach levels of significance. To date, initial evidence indicates the existence of correlations between viral infections during pregnancy and PTD (36)(37)(38). By a recently set up experimental mouse model, it has been demonstrated that viral infections can predispose to bacterial infections, which ultimately lead to PTD (39,40).…”

Liver stem cells: A scientific and clinical perspective

“…In addition, female recipients who have previously produced male offspring may also harbor XY chromosomes further complicating the interpretation of the presence of XY donor cells. 91 Exclusion of fusion events is necessary to determine the true physiological mechanism of repopulation. Bone marrow cells are known to contribute to endothelial cells, myofibroblasts as well as blood cells in the recipient liver.…”

At the crossroads between tolerance and aggression

“…48 During pregnancy, there is evidence that cells with multilineage potential passage between the mother and fetus and can engraft a broad array of tissues in each individual, persisting long after birth. 43,[48][49][50][51] Thus, it is interesting to consider whether the existence of chimerism in human pregnancy may reflect an active process, rather than an accidental event that results from a less than perfect barrier between the mother and fetus. Interestingly, there are situations that have been observed in nature, where cells with multilineage potential traffic between genetically disparate organisms in the same species and establish mixed chimerism.…”