Extracellular vesicles released by keratinocytes regulate melanosome maturation, melanocyte dendricity and pigment transfer

Abstract

Extracellular vesicles (EVs) facilitate the transfer of proteins, lipids and genetic material molecules between cells, and are recognized as an additional mechanism for sustaining intercellular communication. In the epidermis, the communication between melanocytes and keratinocytes is tightly regulated to warrant skin pigmentation. Melanocytes synthetize the melanin pigment in melanosomes that are transported along the dendrites prior to the transfer of melanin pigment to keratinocytes. EVs secreted by keratinocytes modulate pigmentation in melanocytes (Lo Cicero et al., Nat. Comm. 2015). However, whether EVs secreted by keratinocytes contribute to additional processes essential for melanocyte functions remains elusive. Here we show that keratinocyte EVs enhance the ability of melanocytes to generate dendrites, mature melanosomes and their efficient transfer. Further, keratinocyte EVs carrying Rac1 induce important morphological changes, promote dendrite outgrowth, and potentiate melanin transfer to keratinocytes. Hence, in addition to modulate pigmentation, keratinocytes exploit EVs to control melanocyte plasticity and transfer capacity. These data demonstrate that keratinocyte-derived EVs, by regulating melanocyte functions, are major contributors of cutaneous pigmentation and expand our understanding of the mechanism underlying skin pigmentation via a paracrine EV-mediated communication. SIGNIFICANCE STATEMENTOur work uncovers how keratinocyte-derived EVs control melanocyte physiology and functions. By promoting the growth of melanocyte dendrites, maturation, accumulation and peripheral positioning of pigmented melanosomes within the dendrites, and transfer of melanin to keratinocytes, EVs released by keratinocytes control crucial processes in skin photo protection. Importantly, given that dysregulation of these pathways could underlie pigment disorders, melanoma or skin carcinoma, our results open avenues to exploit keratinocyte EVs as tools for the design of new therapies to enhance the ability of melanocytes to provide skin photoprotection, and thus decrease the incidence pigmentary disorders and skin cancers.