New Perspectives on Melanoma_ The Role of PAX3

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Unformatted text preview: ice and human skin both show the existence of skin stem cells in the lower permanent portion of the hair follicle, or bulge [78,192,252]. It is reported that mouse bulge melanocyte stem cells are PAX3‐positive and MITF‐negative [150]; however no reports confirm this to be the case in human skin. In this study we were not able to find such cells. Instead the majority of melanocytes we observed, both in the epidermis and the outer root sheath of the hair follicle, were PAX3 and MITF‐ positive. In contrast to this, the matrix of the hair bulb has far fewer PAX3 and MITF‐positive melanocytes and the base of the hair comprises solely MITF‐positive 68 Chapter III – Medic and Ziman, 2010 (PAX3‐negative) melanocytes. Similarly, the number of PAX3, MLANA‐double‐ labelled melanocytes in the epidermis and ORS were around 60%, but were much lower (around 36%) in the hair matrix. This would indicate that some epidermal melanocytes resemble more the undifferentiated transient amplifying cells of the growing hair rather than differentiated cells of the hair matrix. On the other side of differentiation is the transcription factor HES1, suggested to prevent premature differentiation of melanocytes. Hes1 is reported to be a mediator of Notch signalling in skin development and in hair follicle maintenance where it regulates commitment of epidermal keratinocytes to terminal differentiation [247,253]. Hes1 is expressed in spinous layers and mediates spinous cell gene induction and thus terminal differentiation of epidermal keratinocytes [247]. In a mature hair follicle it is most prominent in the inner root sheath, in matrix cells committed to terminally differentiate to form the hair shaft [246,247]. On the other hand, in the melanocytic lineage, Notch signalling, acting through Hes1, plays a crucial role in survival of immature melanoblasts and melanocyte stem cells, by preventing initiation of apoptosis [194]. Moreover, it prevents differentiation of melanoblasts and melanocyte stem cells before they reach the hair bulb and regulates their proper location in the ORS and in the hair matrix [254]. Therefore it is not surprising that we see a decrease in the number of PAX3 and HES1‐positive cells in the hair bulb compared to the ORS (10.5% and 23.7%, respectively). What is surprising is that around 28% of PAX3‐posi...
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