Dynamic ABCG2 expression in human embryonic stem cells provides the basis for stress response

ABCG2 is a plasmamembrane multidrug transporter with an established role in the cancer drug resistance phenotype. This protein is expressed in various tissues, including several types of stem cells. Although ABCG2 is not essential for life, knock-out mice were found to be hypersensitive to xenobiotics and had reduced levels of the side population of hematopoietic stem cells. Previously we have shown that ABCG2 is present in human embryonic stem cell (hESC) lines while exhibiting a heterogeneous expression pattern. In the present study we examined the role and function of this heterogeneity, and investigated whether it is related to stress responses in hESCs. We did not find any difference between the expression of pluripotency markers in ABCG2 positive and negative hESCs, however, ABCG2 expressing cells had a higher growth rate following cell separation. We found that certain harmful conditions (physical stress, drugs and UV light exposure) are tolerated much better in the presence of ABCG2 protein. This property can be explained by the transporter function which eliminates potential toxic metabolites accumulated during stress conditions. In contrast, mild oxidative stress in hESCs caused a rapid internalization of ABCG2, indicating that certain environmental factors may induce the removal of this transporter from the plasmamembrane. In the light of these results we suggest that a dynamic balance of ABCG2 expression at the population level has an advantage to promptly respond to changes in the cellular environment. Such an actively maintained heterogeneity might be evolutionarily favorable to protect special cell types, including pluripotent stem cells