Melanocytes, melanocyte stem cells, and melanoma stem cells Deborah Lang, PhD, Joseph B. Mascarenhas, PhD, Christopher R. Shea, MD  Clinics in Dermatology  Volume 31, Issue 2, Pages 166-178 (March 2013) DOI: 10.1016/j.clindermatol.2012.08.014 Copyright © 2013 Elsevier Inc. Terms and Conditions

Fig. 1 Models for stem cell growth and progression. For normal tissues as well as tumors, cells may grow in an asymmetrical (hierarchical) or a symmetrical pattern as a method for providing progeny cells for tissue remodeling or tumor growth.15,16 In the hierarchical model, there is a defined subset of cells that are able to self-renew and to give rise to daughter cells. This quality is unidirectional, and if this subset of cells, or the stem cell pool, is depleted, the tissue will be unable to replenish itself. In the stochastic model, all the cells in theory have some ability to behave as a stem cell in terms of self-renewal and multipotential. Extrinsic factors, such as extracellular proteins, growth factors, and other cell types, regulate the cell in terms of decisions for maintenance, differentiation, or cellular death. Clinics in Dermatology 2013 31, 166-178DOI: (10.1016/j.clindermatol.2012.08.014) Copyright © 2013 Elsevier Inc. Terms and Conditions

Fig. 2 Mechanisms for pigmentation loss and hair graying through extrinsic signals. In a hair follicle (shown as a schematic for an anagen follicle), immature melanocytes are located in a stem cell niche within the bulge region of the hair follicle, or in a region defined as the lower permanent portion (LPP).52 Loss of stem cell multipotency occurs when the stem cells fail to differentiate, either permanently or transiently. Although immature melanocytes are still found in the LPP, there is a loss of pigmented melanocytes in the bulbar region of the hair follicle. Loss of stem cell multipotency may be caused by inhibiting Kit receptor signaling53,54 or through loss of canonical Wnt signaling.57 Loss of stem cell self-renewal occurs when the stem cells prematurely differentiate in the LPP and the stem cell pool is depleted. An error in self-renewal first leads to pigmented melanocytes in the LPP, followed by exhaustion of the stem cells and subsequently by a loss of differentiated melanocytes. A loss of melanocyte stem cell self-renewal may be induced by overactive canonical Wnt signaling,57 dysregulation of TGFβ or Notch signaling,64,70-73 or through genotoxic stress.81 Clinics in Dermatology 2013 31, 166-178DOI: (10.1016/j.clindermatol.2012.08.014) Copyright © 2013 Elsevier Inc. Terms and Conditions