Melanin Transfer in the Epidermis: The Pursuit of Skin Pigmentation Control Mechanisms

Abstract

The mechanisms by which the pigment melanin is transferred from melanocytes and processed within keratinocytes to achieve skin pigmentation remain ill-characterized. Nevertheless, several models have emerged in the past decades to explain the transfer process. Here, we review the proposed models for melanin transfer in the skin epidermis, the available evidence supporting each one, and the recent observations in favor of the exo/phagocytosis and shed vesicles models. In order to reconcile the transfer models, we propose that different mechanisms could co-exist to sustain skin pigmentation under different conditions. We also discuss the limited knowledge about melanin processing within keratinocytes. Finally, we pinpoint new questions that ought to be addressed to solve the long-lasting quest for the understanding of how basal skin pigmentation is controlled. This knowledge will allow the emergence of new strategies to treat pigmentary disorders that cause a significant socio-economic burden to patients and healthcare systems worldwide and could also have relevant cosmetic applications.

Keywords: keratinocyte; melanin; melanocore; melanocyte; melanokerasome; melanosome; skin pigmentation.

Figure 1

Proposed models for melanin transfer. (a) Cytophagocytosis: a melanocyte dendrite is phagocytosed, forming a phagolysosome from which melanin granules disperse through the cytoplasm of keratinocytes. (b) Direct membrane fusion: the plasma membranes of both cells fuse, creating a nanotube that allows the passage of melanosomes. (c) Shed vesicles: melanosomes are shed in vesicles from the melanocyte, which fuse with the keratinocyte plasma membrane or are phagocytosed. (d) Coupled exo/phagocytosis: melanin is secreted to the intercellular space through the fusion of the melanosome membrane with the melanocyte plasma membrane and is then phagocytosed by the keratinocyte.

Figure 2

Schematic representation of melanin transfer between melanocytes and keratinocytes in the skin through exo/phagocytosis. After melanosome maturation and transport to the periphery of the melanocyte, Rab11b is recruited to melanosome membranes and the organelle interacts with the exocyst complex to allow melanocore secretion to the extracellular space. Following secretion, melanocores are phagocytosed by keratinocytes in a PAR-2 dependent manner. After internalization by keratinocytes, melanocores follow the endocytic pathway and colocalize with early and late endosomal markers, being stored in mildly acidic and degradative compartments, which we named melanokerasomes, that allow melanin to resist degradation.