Embryonic stem (ES) cells are pluripotent cells derived from the inner cell mass of blastocysts. Under appropriate culture conditions, undifferentiated ES cells can be maintained over many self-renewal cycles without loss of pluripotency 
. Moreover, ES cells are unique in that unlike differentiated cells they do not accumulate DNA damage during multiple self-renewal cycles. This feature is important in vivo
as a small number of ES cells can contribute the whole process of embryogenesis, therefore if DNA damage accumulated in ES cells could potentially affect development of different tissue types.
One of the major causes of DNA damage in cells is reactive oxygen species (ROS). Several studies have shown that low/moderate levels of ROS generated from cell metabolism play an important role in maintenance physiological functions of cells and in some cases are even used as the signaling mediator 
. However, high levels of ROS may cause damages to cell structures, including lipids and membranes, proteins, and DNA, which can in turn lead to apoptosis or senescence 
. In fact, it has been shown that the mutation frequency in ES cells is low because ES cells are sensitive to DNA damage and readily undergo apoptosis or differentiation in order to remove damaged cells from the self-renewal pool 
. Moreover, in order to prevent excessive ROS levels ES cells express high levels of antioxidant defense enzymes as well as high activity of verapamil-sensitive multidrug transporter 
The ATP binding cassette transporter ABCG2 is a verapamil-sensitive multidrug transporter that is expressed in a wide variety of drug-resistant cancer cells, extrudes xenobiotics and certain drugs from cells, thereby mediating drug resistance and affecting the pharmacological behavior of many compounds 
. Later studies determined that ABCG2 expression is not unique to drug resistant cancer cells, but is also expressed in a wide variety of stem cells and in numerous adult tissues 
. In fact, ABCG2 is also the molecular determinant of the side-population (SP) phenotype, which has been widely used for the detection and enrichment of tissue stem cells 
. ABCG2 was also found to be highly expressed in human ES cells 
as well as rhesus monkey ES cells 
. Interestingly despite the clear correlation between ABCG2 and stem cells, its exact function in these cells has not been elucidated.
Recently it has been shown that ABCG2 plays a role in enhancing the survival of haematopoetic stem cells in hypoxia, which is possibly mediated through transportation of heme and porphyrins 
. Heme is composed of iron and protoporphyrin IX (PPIX) which is s an essential component of various hemoproteins, including cytochromes involved in mitochondrial electron transfer chain and in drug metabolism 
. Hemes are also important cofactors in oxygen storage and transport (such as hemoglobin and myoglobin), signaling mediator (nitric oxide synthases, guanylate cyclases) and in regulation of antioxidant-defense enzymes 
. The levels of PPIX in cells are tightly regulated in many cell types as excess PPIX could undergo the iron catalyzed fenton reaction and generate potentially DNA damaging ROS 
. Recently identified heme/porphyrin transporters such as heme carrier protein 1 (HCP1), FLVCR, ABCB6 and ABCG2 are expected to play an important role in maintaining a homeostatic level of porphyrins
Developing embryos naturally resides in hypoxic microenvironments and low level of oxygen regulates cell fate decision of embryonic stem/progenitor cells. Recent work further suggests undifferentiated mouse ES cells adapt their energy metabolism to proliferate at different oxygen tension 
. Cellular adaptations to changes in oxygen levels include stimulating several hypoxia-inducible factors that mediate oxygen homeostasis and control the level of heme, a molecule whose level changes in response to changes in cellular oxygen 
. ABCG2 expression is upregulated under low oxygen conditions, which is consistent with its high expression in tissues exposed to low oxygen environments 
. Since ABCG2 interacts with porphyrin 
and elevated levels of PPIX in erythroid progenitors of ABCG2-deficient mice support the idea that porphyrins are endogenous ABCG2 substrates 
. We speculate PPIX homeostasis in ES cells is maintained by ABCG2 in order to adapt to changes in oxygen availability during rapid colony expansion. However, if ABCG2 function was disrupted, the accumulation of PPIX possibly lead to increased level of ROS would therefore induce DNA damage and then trigger downstream checkpoint signals, which may in turn cause the ES cell to lose its pluripotency as well as disrupting the self-renewal cycle.