-
Pigment Cell & Melanoma Research Sep 2023Vitiligo is caused by an autoimmune reaction against melanocytes leading to melanocyte loss. The cause of vitiligo is an interaction between genetic susceptibility and... (Review)
Review
Vitiligo is caused by an autoimmune reaction against melanocytes leading to melanocyte loss. The cause of vitiligo is an interaction between genetic susceptibility and environmental factors. Both the adaptive immune system-through cytotoxic CD8+ T cells and melanocyte specific antibodies-and the innate immune system are involved in these immune processes in vitiligo. While recent data stressed the importance of innate immunity in vitiligo, the question remains why vitiligo patients' immune response becomes overly activated. Could a long-term increase in innate memory function, described as trained immunity after vaccination and in other inflammatory diseases, play a role as an enhancer and continuous trigger in the pathogenesis of vitiligo? After exposure to certain stimuli, innate immune system is able to show an enhanced immunological response to a secondary trigger, indicating a memory function of the innate immune system, a concept termed trained immunity. Trained immunity is regulated by epigenetic reprogramming, including histone chemical modifications and changes in chromatin accessibility that cause sustained changes in the transcription of specific genes. In responses to an infection, trained immunity is beneficial. However, there are indications of a pathogenic role of trained immunity in inflammatory and autoimmune diseases, with monocytes presenting features of a trained phenotype, resulting in increased cytokine production, altered cell metabolism through mTOR signaling, and epigenetic modifications. This hypothesis paper focusses on vitiligo studies that have shown these indications, suggesting the involvement of trained immunity in vitiligo. Future studies focusing on metabolic and epigenetic changes in innate immune cell populations in vitiligo could help in elucidating the potential role of trained immunity in vitiligo pathogenesis.
Topics: Humans; Vitiligo; Trained Immunity; Immunity, Innate; Immune System; Melanocytes
PubMed: 37293969
DOI: 10.1111/pcmr.13101 -
Biological Reviews of the Cambridge... Feb 2021Hair greying (canities) is one of the earliest, most visible ageing-associated phenomena, whose modulation by genetic, psychoemotional, oxidative, senescence-associated,...
Hair greying (canities) is one of the earliest, most visible ageing-associated phenomena, whose modulation by genetic, psychoemotional, oxidative, senescence-associated, metabolic and nutritional factors has long attracted skin biologists, dermatologists, and industry. Greying is of profound psychological and commercial relevance in increasingly ageing populations. In addition, the onset and perpetuation of defective melanin production in the human anagen hair follicle pigmentary unit (HFPU) provides a superb model for interrogating the molecular mechanisms of ageing in a complex human mini-organ, and greying-associated defects in bulge melanocyte stem cells (MSCs) represent an intriguing system of neural crest-derived stem cell senescence. Here, we emphasize that human greying invariably begins with the gradual decline in melanogenesis, including reduced tyrosinase activity, defective melanosome transfer and apoptosis of HFPU melanocytes, and is thus a primary event of the anagen hair bulb, not the bulge. Eventually, the bulge MSC pool becomes depleted as well, at which stage greying becomes largely irreversible. There is still no universally accepted model of human hair greying, and the extent of genetic contributions to greying remains unclear. However, oxidative damage likely is a crucial driver of greying via its disruption of HFPU melanocyte survival, MSC maintenance, and of the enzymatic apparatus of melanogenesis itself. While neuroendocrine factors [e.g. alpha melanocyte-stimulating hormone (α-MSH), adrenocorticotropic hormone (ACTH), ß-endorphin, corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH)], and micropthalmia-associated transcription factor (MITF) are well-known regulators of human hair follicle melanocytes and melanogenesis, how exactly these and other factors [e.g. thyroid hormones, hepatocyte growth factor (HGF), P-cadherin, peripheral clock activity] modulate greying requires more detailed study. Other important open questions include how HFPU melanocytes age intrinsically, how psychoemotional stress impacts this process, and how current insights into the gerontobiology of the human HFPU can best be translated into retardation or reversal of greying.
Topics: Biology; Hair Color; Hair Follicle; Humans; Melanins; Melanocytes
PubMed: 32965076
DOI: 10.1111/brv.12648 -
Pituitary Dec 2021We present an up-to-date review of all published cases of sellar melanocytoma, a benign melanocytic neoplasm arising from melanocytes present in the leptomeninges... (Review)
Review
PURPOSE
We present an up-to-date review of all published cases of sellar melanocytoma, a benign melanocytic neoplasm arising from melanocytes present in the leptomeninges surrounding the pituitary.
METHODS
Both the Medline and Embase databases were searched for case reports or case series of patients with a sellar mass consisting of melanocytes.
RESULTS
All 14 identified patients developed symptoms due to compression of the surrounding structures. Symptoms included pituitary dysfunction and visual impairment. All patients received a transsphenoidal resection as first-line treatment. The diagnosis is made on pathological examination but deciding whether a sellar melanocytic tumor is best classified as a melanocytoma or a melanoma is not straightforward.
DISCUSSION
Genetic analyses can help differentiate between central nervous system origin and metastasis of a cutaneous melanoma with the presence of a GNAQ and GNA11 mutations or a BRAF mutation, respectively. First choice treatment is complete resection, and in case of incomplete resection or recurrence additional radiotherapy is advised.
Topics: Humans; Melanocytes; Melanoma; Mutation; Pituitary Gland; Skin Neoplasms
PubMed: 34518998
DOI: 10.1007/s11102-021-01186-9 -
Acta Dermato-venereologica Jun 2020Cutaneous melanoma arises from melanocytes following genetic, epigenetic and allogenetic (i.e. other than epi/genetic) modifications. An estimated 10% of cutaneous... (Review)
Review
Cutaneous melanoma arises from melanocytes following genetic, epigenetic and allogenetic (i.e. other than epi/genetic) modifications. An estimated 10% of cutaneous melanoma cases are due to inherited variants or de novo mutations in approximately 20 genes, found using linkage, next-generation sequencing and association studies. Based on these studies, 3 classes of predisposing melanoma genes have been defined based on the frequency of the variants in the general population and lifetime risk of developing a melanoma: (i) ultra-rare variants with a high risk, (ii) rare with a moderate risk, and (iii) frequent variants with a low risk. Most of the proteins encoded by these genes have been shown to be involved in melanoma initiation, including proliferation and senescence bypass. This paper reviews the role(s) of these genes in the transformation of melanocytes into melanoma. It also describes their function in the establishment and renewal of melanocytes and the biology of pigment cells, if known.
Topics: Animals; Biomarkers, Tumor; Cell Lineage; Genetic Predisposition to Disease; Humans; Melanins; Melanocytes; Melanoma; Melanosomes; Mutation; Mutation Rate; Phenotype; Risk Assessment; Risk Factors; Skin Neoplasms; White People
PubMed: 32346747
DOI: 10.2340/00015555-3494 -
Frontiers in Immunology 2021Vitiligo is an acquired multifactorial disease that affects melanocytes and results in skin depigmentation. In this review, we examine the role of cells stress and... (Review)
Review
Vitiligo is an acquired multifactorial disease that affects melanocytes and results in skin depigmentation. In this review, we examine the role of cells stress and self-reactive T cells responses. Given the canonical and non-canonical functions of NKG2D, such as authenticating stressed target and enhance TCR signaling, we examine how melanocyte stress leads to the expression of ligands that are recognized by the activating receptor NKG2D, and how its signaling results in the turning of T cells against self (melanocyte suicide by proxy). We also discuss how this initiation phase is followed by T cell perpetuation, as NKG2D signaling results in self-sustained long-lasting T cells, with improved cytolytic properties.
Topics: Animals; Autoimmunity; CD8-Positive T-Lymphocytes; Cellular Microenvironment; Cytotoxicity, Immunologic; Humans; Melanocytes; NK Cell Lectin-Like Receptor Subfamily K; Oxidative Stress; Signal Transduction; Skin; Skin Pigmentation; Vitiligo
PubMed: 33717132
DOI: 10.3389/fimmu.2021.624131 -
Biomolecules Dec 2022Melanogenesis is a major part of the environmental responses and tissue development of the integumentary system. The balance between reduction and oxidation (redox)... (Review)
Review
Melanogenesis is a major part of the environmental responses and tissue development of the integumentary system. The balance between reduction and oxidation (redox) governs pigmentary responses, for which coordination among epidermal resident cells is indispensable. Here, we review the current understanding of melanocyte biology with a particular focus on the "master regulator" of oxidative stress responses (i.e., the Kelch-like erythroid cell-derived protein with cap'n'collar homology-associated protein 1-nuclear factor erythroid-2-related factor 2 system) and the autoimmune pigment disorder vitiligo. Our investigation revealed that the former is essential in pigmentogenesis, whereas the latter results from unbalanced redox homeostasis and/or defective intercellular communication in the interfollicular epidermis (IFE). Finally, we propose a model in which keratinocytes provide a "niche" for differentiated melanocytes and may "imprint" IFE pigmentation.
Topics: NF-E2-Related Factor 2; Epidermis; Melanocytes; Oxidative Stress; Antioxidants
PubMed: 36671405
DOI: 10.3390/biom13010020 -
Dermatology (Basel, Switzerland) 2023Vitiligo is a common depigmentation skin disease associated with significant psychosocial morbidity and profound effect on the quality of life. The treatment of vitiligo...
BACKGROUND
Vitiligo is a common depigmentation skin disease associated with significant psychosocial morbidity and profound effect on the quality of life. The treatment of vitiligo is still a major challenge in the field of dermatology. Currently, topical steroids, calcineurin inhibitors, ultraviolet phototherapy, surgery, and cultured and non-cultured epidermal melanocyte transplantation are used for the treatment of vitiligo. However, the effectiveness of these treatment modalities is limited by the lack of response, long-term treatment periods, high cost, and inevitable adverse effects.
OBJECTIVES
In this study, we aimed to evaluate the efficacy of intraepidermal injection of autologous non-cultured melanocytes and keratinocytes as an alternative therapy for the refractory and stable (RS) vitiligo.
METHODS
The treatment procedure was performed on thirty-nine RS vitiligo patients. The autologous skin grafts obtained from the buttock area and epidermis were separated from dermis using dispase. Single-cell autologous melanocytes and keratinocytes were prepared from the epidermis by trypsin/ethylene diamine tetra acetic acid and injected at the concentration of 100-400 × 103 cells/cm2, intra-epidermally to the selected vitiligo lesions. Vitiligo re-pigmentation was monitored employing photography. Photographs were taken prior to and 2, 4, and 6 months after the cell transplantation. Improvement of the skin depigmentation was classified as follows: <25% as minimal response, 26-50% as moderate response, 51-75% as good response, and finally 76-100% as excellent response.
RESULTS
Cell infusion appeared to be safe as none of the patients exhibited any adverse effects. At the end of the sixth month follow-up period, of the treated patients, 12.8% demonstrated an excellent response, 36% exhibited a good response, and 51.2% showed a moderate to minimal response to the administered therapy. Obtained significant p value for Wilcoxon test over the checkpoints at 2nd, 4th, and 6th month (p = 0.03, 0.04, and 0.039, respectively) post-cell transplantation confirmed notable growing trend in the re-pigmentation.
CONCLUSION
Our findings provide a strong support for the therapeutic efficacy of autologous non-cultured melanocytes and keratinocytes in patients with RS vitiligo.
Topics: Humans; Vitiligo; Quality of Life; Treatment Outcome; Keratinocytes; Melanocytes
PubMed: 37573775
DOI: 10.1159/000533353 -
Expert Opinion on Therapeutic Targets Mar 2023The treatment of vitiligo remains challenging due to the complexity of its pathogenesis, influenced by genetic factors, oxidative stress and abnormal cell adhesion that... (Review)
Review
INTRODUCTION
The treatment of vitiligo remains challenging due to the complexity of its pathogenesis, influenced by genetic factors, oxidative stress and abnormal cell adhesion that collectively impact melanocyte survival and trigger immune system attacks, resulting in melanocyte death. Melanocytes in vitiligo are believed to exhibit genetic susceptibility and defects in cellular mechanisms, such as defects in autophagy, that reduce their ability to resist oxidative stress, leading to increased expression of the pro-inflammatory protein HSP70. The low expression of adhesion molecules, such as DDR1 and E-cadherin, accelerates melanocyte damage and antigen exposure. Consequently, autoimmune attacks centered on IFN-γ-CXCR9/10-CXCR3-CD8 T cells are initiated, causing vitiligo.
AREAS COVERED
This review discusses the latest knowledge on the pathogenesis of vitiligo and potential therapeutic targets from the perspective of suppressing autoimmune attacks and activating melanocytes functions.
EXPERT OPINION
Vitiligo is one of the most challenging dermatological diseases due to its complex pathogenesis with diverse therapeutic targets. Immune suppression, such as corticosteroids and emerging JAK inhibitors, has proven effective in disease progression. However, during the early stages of the disease, it is also important to optimize therapeutic strategies to activate melanocytes for alleviating oxidative stress and improving treatment outcomes.
Topics: Humans; Vitiligo; CD8-Positive T-Lymphocytes; Melanocytes; Oxidative Stress
PubMed: 36947026
DOI: 10.1080/14728222.2023.2193329 -
Experimental Dermatology Aug 2021Melanocytes originate in the neural crest as precursor cells which then migrate and proliferate to reach their destination where they differentiate into... (Review)
Review
Melanocytes originate in the neural crest as precursor cells which then migrate and proliferate to reach their destination where they differentiate into pigment-producing cells. Melanocytes not only determine the colour of hair, skin and eyes but also protect against the harmful effects of UV irradiation. The establishment of the melanocyte lineage is regulated by a defined set of transcription factors and signalling pathways that direct the specific gene expression programmes underpinning melanoblast specification, survival, migration, proliferation and differentiation. In addition, epigenetic modifiers and replacement histones play key roles in regulating gene expression and its timing during the different steps of this process. Here, we discuss the evidence for the role of epigenetic regulators in melanocyte development and function and how they interact with transcription factors and signalling pathways to establish and maintain this important cell lineage.
Topics: Animals; Cell Lineage; Epigenesis, Genetic; Homeostasis; Humans; Melanocytes; Mice; Transcription Factors
PubMed: 34003523
DOI: 10.1111/exd.14391 -
Nature Communications Jun 2023Melanoma exhibits numerous transcriptional cell states including neural crest-like cells as well as pigmented melanocytic cells. How these different cell states relate...
Melanoma exhibits numerous transcriptional cell states including neural crest-like cells as well as pigmented melanocytic cells. How these different cell states relate to distinct tumorigenic phenotypes remains unclear. Here, we use a zebrafish melanoma model to identify a transcriptional program linking the melanocytic cell state to a dependence on lipid droplets, the specialized organelle responsible for lipid storage. Single-cell RNA-sequencing of these tumors show a concordance between genes regulating pigmentation and those involved in lipid and oxidative metabolism. This state is conserved across human melanoma cell lines and patient tumors. This melanocytic state demonstrates increased fatty acid uptake, an increased number of lipid droplets, and dependence upon fatty acid oxidative metabolism. Genetic and pharmacologic suppression of lipid droplet production is sufficient to disrupt cell cycle progression and slow melanoma growth in vivo. Because the melanocytic cell state is linked to poor outcomes in patients, these data indicate a metabolic vulnerability in melanoma that depends on the lipid droplet organelle.
Topics: Animals; Humans; Lipid Droplets; Zebrafish; Melanoma; Melanocytes; Fatty Acids; Lipid Metabolism
PubMed: 37268606
DOI: 10.1038/s41467-023-38831-9