Melanocytes
Melanocytes: skin’s defenders against sun damage and germs
Credit: Art by Nelli Aghekyan. Set in motion by Dr. Emanuele Petretto. Words by Dr. Nowrin Ahmed. Project Coordinator: Dr. Masia Maksymowicz. Series Director: Dr. Radhika Patnala
#Extraordinarycelltypes #sciart #lifescience
Melanocytes add colour to life
Melanocytes, also known as pigment cells, contribute to the brilliant colours we see in the fur, feathers, and skin of animals. They produce the pigment melanin whose name is derived from the Greek word ‘melas’ meaning black, and is responsible for the colour of skin, hair, and eyes in humans. They are found in the epidermis and hair follicles of the skin, the largest organ in the body. Melanocytes also inhabit the mucosa, inner ear, and brain, as well as other tissues in humans where they perform various functions [1]. There are two types of melanin: eumelanin (dark brown and black) and pheomelanin (yellow, red, and light brown). Melanin is synthesized in a biochemical pathway known as melanogenesis [2, 3]. This process occurs in organelles called melanosomes, where melanin is later stored. Mutations in this pathway lead to pigmentation disorders such as melasma, oculocutaneous albinism and vitiligo [4].
Diversity in melanin and skin colour
Eumelanin and pheomelanin differ in size, shape, and proportion within melanosomes, although the number of melanocytes (which is 1200 per mm2 of the skin) remains the same in all humans [5]. The variation in skin pigmentation in different ethnic groups is conserved and depends on the proportion of eumelanin in melanosomes [6, 7]. On the other hand, pheomelanin levels do not determine skin pigmentation [8]. Melanosomes that contain darker pigment (eumelanin) provide better protection against UVR damage than the lighter pigment (pheomelanin) because eumelanin is resistant to degradation and oxidative stress, which is also why there is a lower incidence of skin cancer in populations with darker skin tone [7, 9].
Melanocytes are not the only melanin-producing cells in the human body. Retinal pigment epithelial cells found in the iris can also produce melanin that gives rise to human eye color and protects the retina from UVR damage [10].
Cooperation with other skin cell types
Melanocytes, which comprise 3–7% of epithelial cells [11], are located in the basal layer of the epidermis and are wedged between keratinocytes which in turn comprises 90% of epithelial cells [12]. Melanocytes and keratinocytes form a functional unit called ‘the epidermal melanin unit’ where each melanocyte transfers melanin to 30–40 keratinocytes through branch-like protrusions known as dendrites [13]. Dendrites from melanocytes actively move in search of neighboring keratinocytes that are devoid of melanin to export melanin to keratinocytes, thus adding pigmentation to keratinocytes [1]. Melanin also provides essential protection against UVR-induced DNA damage in keratinocytes by forming a cover over the nucleus [9, 14] The mechanisms through which melanin is transferred and managed in keratinocytes are not fully understood [15]. However, several studies showed that keratinocytes not only receive melanin from melanocytes, but also can regulate vital functions in melanocytes such as the production and transfer of melanin [16]. Therefore, melanocytes engage in a symbiotic relationship with keratinocytes to maintain skin pigmentation and shield it from the harmful effects of UVR.
Melanocytes under the sun
Repeated exposure to UVR can lead to DNA damage, sunburn and tanning in the epidermis. Melanocytes are the first line of defense for the epidermis against sun damage [17]. Melanin, especially the darker pigment (eumelanin), shields the skin by forming a physical barrier that scatters and absorbs UVR, thus reducing the penetration of UVR through the epidermis [18]. UVR exposure also increases the number of dendrites in melanocytes, as well as the production and transfer of melanosomes to keratinocytes [19, 20]. This increase in melanin causes skin darkening known as the tanning response which can happen within a few seconds to days after sun exposure [21, 22]. Interestingly, tanning is also determined by paracrine factors such as α-melanocyte stimulating hormone (α-MSH) from neighboring keratinocytes which induces melanogenesis [16]. Additionally, α-MSH also shelters melanocytes from UVR-induced DNA damage by increasing nucleotide excision repair and maintaining chromosome stability in melanocytes [23, 24]. In fact, individuals with a defect in the gene encoding α-MSH are at a higher risk for melanoma [25].
Melanocytes fight pathogens
A lesser-known function of melanocytes is that they protect the skin against pathogens by detecting bacteria or viruses, and recruiting immune cells such as neutrophils, macrophages, and T-cells by secreting pro-inflammatory cytokines and chemokines [26]. Interestingly, melanocytes can detect pathogens with pattern-recognition receptors called Toll-like receptors (TLR 2–4, 7 and 9), produce pro-inflammatory cytokines (IL-6 and Il-8) [27], and perform phagocytosis, just like immune cells [28] Additionally, the cytokine interferon, which is involved in viral infections, is produced in melanocytes [29], providing further evidence that melanocytes can defend the skin against viruses.
Melanocytes in cancer
Since skin cancer is the most common type of cancer, melanocytes are extensively studied. For example, it was shown that damage to melanocytes leads to a fatal skin cancer known as melanoma, and its occurrence is rapidly increasing in the global population [30]. In fact, increased sun exposure greatly increases the risk of melanoma [31] which is fatal because this cancer type does not respond to treatments such as chemotherapy and radiotherapy [32]. A recent study has shown that melanoma may arise from undifferentiated melanocyte stem cells (McSCs) found in the hair follicles [33]. On the other hand, when UVR or physical injury damages the skin, McSCs in the hair follicular bulb differentiate into melanocytes and move to the epidermis to replace damaged melanocytes [34]. The mechanisms that cause McSCs to become malignant are key to uncovering ways to prevent and treat melanoma. Melanocytes found in hair follicles are responsive to aging and die at the end of the hair cycle (3–8 years) whereas epidermal melanocytes are resistant to cell death [35]. Long life cycle of melanocytes might make them more susceptible to mutations.
Future studies need to examine how melanocytes, which are specialized to protect the skin, can transform to melanoma skin cancer.
Recognizing and appreciating the labs working in this space
- Mayumi Ito Lab, The Ronald O. Perelman Department of Dermatology at New York University School of Medicine, New York, USA. https://med.nyu.edu/faculty/mayumi-ito-suzuki
- Zalfa Abdel-Malek lab, Department of Dermatology, University of Cincinnati College of Medicine, Cincinnati, Ohio, US https://med.uc.edu/landing-pages/profile/Index/Pubs/abdelmza
- Raymond E. Boissy lab, Department of Dermatology, University of Cincinnati College of Medicine, Cincinnati, Ohio, US https://med.uc.edu/education/medical-student-education/research/mentor-profile/Index/Pubs/boissyre
- Meenhard Herlyn lab, Molecular and Cellular Oncogenesis Program, Melanoma Research Center, The Wistar Institute, Philadelphia, Pennsylvania, USA, https://www.wistar.org/our-scientists/meenhard-herlyn/ , Twitter: @HerlynLab , Facebook: https://www.facebook.com/profile.php?id=100063871759874,
- Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA https://ccr.cancer.gov/laboratory-of-cell-biology
- Marks Lab, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA https://www.med.upenn.edu/markslab/ , Twitter: @marks_labCHOP
- The Tobin Lab, UCD Charles Institute of Dermatology, University College Dublin, Belfield, Dublin 4, Ireland https://www.ucd.ie/charles/research/researchgroups/thetobingroup/ , Twitter: @CharlesUCD
- Structure and Membrane Compartments, Cell biology and Cancer (UMR144), Institut Curie, PSL Research University, CNRS, Paris, France, https://institut-curie.org/team/raposo
- The Richard White Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York, USA https://www.mskcc.org/research/ski/labs/richard-white , Twitter: @whitefishlab
- Ceol Lab, Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA https://www.ceollab.com/index.html
- Fisher Laboratory, Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts, USA. https://www.massgeneral.org/dermatology/research/cutaneous-biology-research-center/faculty-labs/david-fisher-lab , Twitter: @FisherLabMGH
References
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2. Pavel, S. “Dynamics of melanogenesis intermediates.” J Invest Dermatol 100.2 Suppl (1993): 162s-65s.
3. Kondo, T., and V. J. Hearing. “Update on the regulation of mammalian melanocyte function and skin pigmentation.” Expert Rev Dermatol 6.1 (2011): 97–108.
4. Yamaguchi, Y., and V. J. Hearing. “Melanocytes and their diseases.” Cold Spring Harb Perspect Med 4.5 (2014).
5. Staricco, R. J., and H. Pinkus. “Quantitative and qualitative data on the pigment cells of adult human epidermis.” J Invest Dermatol 28.1 (1957): 33–45.
6. Cichorek, M., et al. “Skin melanocytes: biology and development.” Postepy Dermatol Alergol 30.1 (2013): 30–41.
7. Centeno, P. P., V. Pavet, and R. Marais. “The journey from melanocytes to melanoma.” Nat Rev Cancer 23.6 (2023): 372–90.
8. Thody, A. J., et al. “Pheomelanin as Well as Eumelanin Is Present in Human Epidermis.” J Invest Dermatol 97 2 (1991): 340–4.
9. Abdel-Malek, Z. A., A. L. Kadekaro, and V. B. Swope. “Stepping up Melanocytes to the Challenge of Uv Exposure.” Pigment Cell Melanoma Res 23 2 (2010): 171–86.
10. Hu, D. N., J. D. Simon, and T. Sarna. “Role of Ocular Melanin in Ophthalmic Physiology and Pathology.” Photochem Photobiol 84 3 (2008): 639–44.
11. Hsu, M. Y., and M. Herlyn. “Cultivation of Normal Human Epidermal Melanocytes.” Methods Mol Med 2 (1996): 9–20.
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19. Friedmann, P. S., and B. A. Gilchrest. “Ultraviolet Radiation Directly Induces Pigment Production by Cultured Human Melanocytes.” J Cell Physiol 133 1 (1987): 88–94.
20. Boissy, R. E. “Melanosome Transfer to and Translocation in the Keratinocyte.” Exp Dermatol 12 Suppl 2 (2003): 5–12.
21. Routaboul, C., A. Denis, and A. Vinche. “Immediate Pigment Darkening: Description, Kinetic and Biological Function.” Eur J Dermatol 9 2 (1999): 95–9.
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23. Li, X., et al. “The Protective Role of Mc1r in Chromosome Stability and Centromeric Integrity in Melanocytes.” Cell Death Discov 7 1 (2021): 111.
24. Seoane, M., et al. “Lineage-Specific Control of Tfiih by Mitf Determines Transcriptional Homeostasis and DNA Repair.” Oncogene 38 19 (2019): 3616–35.
25. Song, X., et al. “Alpha-Msh Activates Immediate Defense Responses to Uv-Induced Oxidative Stress in Human Melanocytes.” Pigment Cell Melanoma Res 22 6 (2009): 809–18.
26. Gasque, P., and M. C. Jaffar-Bandjee. “The Immunology and Inflammatory Responses of Human Melanocytes in Infectious Diseases.” J Infect 71 4 (2015): 413–21.
27. Yu, N., et al. “Cultured Human Melanocytes Express Functional Toll-Like Receptors 2–4, 7 and 9.” J Dermatol Sci 56 2 (2009): 113–20.
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29. Satomi, H., et al. “Interferon-Beta from Melanoma Cells Suppresses the Proliferations of Melanoma Cells in an Autocrine Manner.” Cytokine 18 2 (2002): 108–15.
30. Linos, E., et al. “Increasing Burden of Melanoma in the United States.” J Invest Dermatol 129 7 (2009): 1666–74.
31. Suppa, M., et al. “Association of Sunbed Use with Skin Cancer Risk Factors in Europe: An Investigation within the Euromelanoma Skin Cancer Prevention Campaign.” J Eur Acad Dermatol Venereol 33 Suppl 2 (2019): 76–88.
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About the author:
Dr. Nowrin Ahmed
Content Editor The League of Extraordinary Cell Types, Sci-Illustrate Stories
Dr. Nowrin Ahmed has a PhD in Behavioral and Neural Sciences from Rutgers University-Newark (NJ, USA) where she studied the interactions between the midline thalamus and the amygdala. Currently, she is a post-doctoral fellow at Rutgers University — Newark where she is studying amygdala circuits. Dr. Nowrin enjoys sharing the beauty of science with diverse audiences.
About the artist:
NELLY AGHEKYAN
Contributing Artist The League of Extraordinary Cell Types, Sci-Illustrate Stories
Nelli Aghekyan, did a bachelor’s and master’s in Architecture in Armenia, after studying architecture and interior design for 6 years, she concentrated on her drawing skills and continued her path in the illustration world. She works mainly on children’s book illustrations, some of her books are now being published. Currently living in Italy, she works as a full-time freelance artist, collaborating with different companies and clients.
About the animator:
DR. EMANUELE PETRETTO
Animator The League of Extraordinary Cell Types, Sci-Illustrate Stories
Dr. Petretto received his Ph.D. in Biochemistry at the University of Fribourg, Switzerland, focusing on the behavior of matter at nanoscopic scales and the stability of colloidal systems. Using molecular dynamics simulations, he explored the delicate interaction among particles, interfaces, and solvents.
Currently, he is fully pursuing another delicate interaction: the intricate interplay between art and science. Through data visualization, motion design, and games, he wants to show the wonders of the complexity surrounding us.
About the series:
The League of Extraordinary Cell types
The team at Sci-Illustrate and Endosymbiont bring to you an exciting series where we dive deep into the wondrous cell types in our body, that make our hearts tick ❤.
