Oral communication, iL45

Official XXIst International Pigment Cell Conference website - 21-24 Sept 2011, Bordeaux - France | updated: September 04 2011

The human hair-bulb melanocyte: a model aging system for both our gray hair and our gray matter?

Nature re-uses protective and defensive systems in complex organisms at both local and systemic levels, and often with remarkable self-similarity. Perhaps this is not too surprising where benefit is proven first at the local level/periphery, and where similar components of these systems are then reused during evolution in phylogenetically more highly-developed organisms with a central nervous system. A case in point is the co-utilization of similar melanocortin and opioid systems by central neurons and their peripheral neuro-ectodermal cousins - the melanocytes. We recently described in some detail this self-similarity for corticotrophin-releasing factor, pro-opiomelanocortin (POMC)-derived melanocortins (α-melanocyte stimulating hormone and adrenocorticotropic hormone), and the POMC-derived opioid β-endorphin in the hair follicle pigmentary unit. As long-living postmitotic neural crest-derived cells, epidermal melanocytes share several features with neurons such as dendritic morphology, utilization of tyrosine (melanins in epidermal melanocytes and catecholamines in neurons), expression of neuropeptides, neurohormones, neurotransmitters and a receptor profile that includes melanocortin receptors, adrenoreceptors, and neurotrophin receptors. Within this context, we are keen to understand how age-associated pigment cell decline and cognitive decline may be ‘physiologic’ when due to mild functional deficit or pathologic when associated with more severe (neuro)degenerative change. The former could involve subtle effects (e.g., synaptic alterations in neurons or modulation of melanocyte-keratinocyte crosstalk), while the latter involves significant neuronal or melanocyte loss through for example apoptosis. Although clearly trivial by comparison with neurodegeneration, aging individuals also exhibit ‘senile’ white hair or canities. Despite our increasing insights of the (co)regulation of melanocyte and epithelial stem cells in the hair follicle from murine studies, we know little about how death signaling in neural crest-derived cells is triggered ‘physiologically’ (eg. catagen or hair follicle regression) and how this differs from dysregulated or pathologic states (e.g. neurodegenerative disorders, canities, vitilgo). Given the relatedness of neurons and melanocytes, this author proposes that the hair follicle pigmentary unit is uniquely placed to unravel some of the mechanisms of neuronal cell aging and degeneration. Despite their common cutaneous origin hair follicle melanocytes appear to be more sensitive to aging influences than melanocytes in the epidermis, as evidenced by the slow loss of pigment tone with age in the epidermis contrasting with the marked dilution of hair color in canities. This is likely to reflect significant differences in the epidermal and follicular melanocyte microenvironments. Not only is there tight coupling of follicular pigmentation to the hair growth cycle, but there are also differences in stem cell niche capacity, niche exposure, and perhaps in the overriding effects of a dominant inheritance. The hair follicle may provide richer information in this context, as the life-histories of its various sub-populations of follicular melanocytes is very diverse. Pre-proliferative, proliferative, differentiated, terminally-differentiated and ‘senescent‘ melanocytes all co-exist in the same growing hair follicle. Thus, there may be several roads that can lead to canities in the human (compared perhaps to mouse) hair follicle, especially when loss of pigmentation occurs within the same single anagen VI sub-stage of the hair growth cycle. Such scenarios could involve a plethora of potential aggressors for melanocytes, which may be similar to those experienced by other neural crest-derived cells. Damage may result due to variable capacity to accumulate, withstand, inactivate (oxidative) stress associated with either endogenous [e.g., ‘physiologically-cytotoxic’ (neuro) melanogenesis and aging] or exogenous [e.g., (geno)toxic stresses] insults. The availability of human hair follicle melanocyte culture methods has provided some impetus to dissecting the regulation of melanogenesis in the human hair follicle. However, neuronal models for research in neurogenerative disease have significant limitations as a result of their non-human origin and/or transformed state. Previously, Gilchrest and Yaar proposed the human epidermal melanocyte from neonatal foreskin as a model system for Alzheimer’s disease research. These researchers found that pigment cells underwent apoptosis (like neurons) in the presence of β-amyloid. Moreover, they found that β-amyloid is a ligand for the 75-kD transmembrane neurotrophin receptor (a member of the family of apoptotic receptors). We have extended these studies to show that amyloidogenic isoforms of amyloid precursor protein and β-amyloid1-40 can be detected in adult human skin melanocytes obtained from elderly donors. Incubation of these cells with aggregated β-amyloid1-40 peptide caused a concentration-dependent reduction in their viability, whereas age-matched dermal fibroblasts remained unaffected. Here we propose that the aging hair follicle pigmentary unit of scalp hair follicles could provide a most useful surrogate for studying age-associated neural cell decline, both of melanocytes and neural cells in general, including those with mechanisms involving amyloidogenic isoforms of amyloid precursor protein and the β-amyloid1-40 peptide.

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