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Do ABC transporters protect human hair follicles and their epithelial progenitor populations from xenobiotic insult?

IS Haslam, H Faruqi, C El Chami, A Shahmalak, R Paus

ABC transporters are widely understood to act as a pharmacological barrier to the movement of toxins and drugs. Certain members of this superfamily (i.e. ABCB1 and ABCG2) are also expressed in certain stem cell populations, conferring the side-population (SP) phenotype by excluding the nucleic acid marker Hoechst 33342. Within the human hair follicle, little is known about the expression or functions of these transporters and although it is well established that the hair follicle contains an epithelial stem cell population, the presence of ABC proteins is unknown. Within the hair follicle, proliferative progenitor cells in the hair matrix are highly susceptible to cytotoxic damage during chemotherapy treatment. As such, the expression of ABC transporters would be biological beneficial in protecting these vital hair follicle cell populations. This study therefore aimed to assess the expression and localisation of several ABC transporters within the human hair follicle and provide preliminary evidence as to their functional significance.

Quantitative PCR analysis was used to determine ABC gene expression. Immunofluorescent staining of ABC transporters and stem cell markers was used to confirm expression and localisation. Functional activity was probed using the ABCB1/G2 substrate dye, Hoechst 33342. The impact of ABC-mediated transport on cytotoxic damage caused by chemotherapy exposure was investigated using the cyclophosphamide metabolite, 4-hydroxycyclophosphamide (4-HC). Impact on hair growth, proliferation, apoptosis, pigmentation and P53 expression was investigated.

Numerous members of the ABC transporter superfamily were expressed at the mRNA level in human hair follicles. Expression of xenobiotic ABC transporters (ABCB1, ABCC4, ABCG2) varied, with ABCG2 expression primarily restricted to the stem cell region and matrix keratinocytes. Hoechst 33342 was excluded from the stem cell region, with accumulation increasing following inhibition of both ABCB1 and ABCG2 (using verapamil and Ko143, respectively). Inhibition of ABCG2 (using Ko143) resulted in further retardation of hair growth and increased hair follicle regression, following 4-HC exposure. We report that numerous ABC transporters are expressed in the human hair follicle and that certain members are functionally active in important cell populations. Current evidence suggests that ABCG2 may modulate the hair follicle response to cytotoxic agents.

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