Melanocyte Regeneration Research Articles

Management of the refractory vitiligo patient: current therapeutic strategies and future options.

Vitiligo is an autoimmune disease that leads to disfiguring depigmented lesions of skin and mucosa. Although effective treatments are available for vitiligo, there are still some patients with poor responses to conventional treatment. Refractory vitiligo lesions are mostly located on exposed sites such as acral sites and lips, leading to significant life stress. Understanding the causes of refractory vitiligo and developing targeted treatments are essential to enhance vitiligo outcomes. In this review, we summarized recent treatment approaches and some potential methods for refractory vitiligo. Janus kinase inhibitors have shown efficacy in refractory vitiligo. A variety of surgical interventions and fractional carbon dioxide laser have been widely applied to combination therapies. Furthermore, melanocyte regeneration and activation therapies are potentially effective strategies. Patients with refractory vitiligo should be referred to psychological monitoring and interventions to reduce the potential pathogenic effects of chronic stress. Finally, methods for depigmentation and camouflage may be beneficial in achieving uniform skin color and improved quality of life. Our ultimate focus is to provide alternative options for refractory vitiligo and to bring inspiration to future research.

Canonical Wnt and TGF-β/BMP signaling enhance melanocyte regeneration but suppress invasiveness, migration, and proliferation of melanoma cells.

Melanoma is the deadliest form of skin cancer and develops from the melanocytes that are responsible for the pigmentation of the skin. The skin is also a highly regenerative organ, harboring a pool of undifferentiated melanocyte stem cells that proliferate and differentiate into mature melanocytes during regenerative processes in the adult. Melanoma and melanocyte regeneration share remarkable cellular features, including activation of cell proliferation and migration. Yet, melanoma considerably differs from the regenerating melanocytes with respect to abnormal proliferation, invasive growth, and metastasis. Thus, it is likely that at the cellular level, melanoma resembles early stages of melanocyte regeneration with increased proliferation but separates from the later melanocyte regeneration stages due to reduced proliferation and enhanced differentiation. Here, by exploiting the zebrafish melanocytes that can efficiently regenerate and be induced to undergo malignant melanoma, we unravel the transcriptome profiles of the regenerating melanocytes during early and late regeneration and the melanocytic nevi and malignant melanoma. Our global comparison of the gene expression profiles of melanocyte regeneration and nevi/melanoma uncovers the opposite regulation of a substantial number of genes related to Wnt signaling and transforming growth factor beta (TGF-β)/(bone morphogenetic protein) BMP signaling pathways between regeneration and cancer. Functional activation of canonical Wnt or TGF-β/BMP pathways during melanocyte regeneration promoted melanocyte regeneration but potently suppressed the invasiveness, migration, and proliferation of human melanoma cells in vitro and in vivo. Therefore, the opposite regulation of signaling mechanisms between melanocyte regeneration and melanoma can be exploited to stop tumor growth and develop new anti-cancer therapies.

Is The Glycerol, Petroleum Jelly and Liquid Paraffin Mixture (Dexeryl®) an Adjunctive Therapy for Vitiligo of Autoimmune Origin? Toward a Novel Therapeutic Indication. About a Case

Introduction: Vitiligo, considered to have an autoimmune basis, is an acquired, non-contagious disorder characterized by progressive, patchy loss of pigmentation from skin, overlying hair, and oral mucosa. The treatment of vitiligo includes medicines or medicated skin creams, such as corticosteroids or a calcineurin inhibitor, phototherapy, Depigmentation, or removing color from dark areas, surgical techniques. The results from treatments can vary from one part of the body to another, and new patches may appear in the meantime Here, we report a case with complete remission of vitiligo of autoimmune origin under DMARDs and the glycerol, petroleum jelly and liquid paraffin mixture (dexeryl®), of which we hypothesize that the glycerol, petroleum jelly and liquid paraffin mixture (dexeryl®) would have played a role in rapid and complete vitiligo lesion regression. Clinical Observation: An 18-year-old Malian female presented to the internal medicine outpatient clinic with 3-months history of pruritic achromic skin patches. Concomitantly, this was associated with Gottron's papules, polyarthralgia with arthritis and exertional dyspnea for which the diagnosis of mixed connective tissue disease (MTCD) based on the EULAR/ACR 2019 criteria for systemic lupus erythematosus, EULAR/ACR 2010 criteria for rheumatoid arthritis with subcutaneous rheumatoid nodule, EULAR/ ACR 2013 criteria for systemic scleroderma, Bohan and Peter 1975 criteria for probable dermato-polymyositis and Kasukawa’s criteria 1988 for MTCD itself; and autoimmune hemolytic anemia (AHA) with positivity of the direct coombs test and the context of hemolysis were made. Vitiligo of autoimmune origin was considered because of the clinical context and the immunological disorder in this case. She was treated only with Disease-Modifying Anti-rheumatic Drugs (DMARDs) and glycerol, petroleum jelly and liquid paraffin mixture (dexeryl®). The vitiligo lesion had completely resolved on 1-year follow-up visit in our case without specific vitiligo treatment. Discussion: The glycerol, petroleum jelly and liquid paraffin mixture (dexeryl®) in our case was indicated for dry skin presentation. But we observed a rapid and complete vitiligo regression under this mixture associated with DMARDs. This is why, beside a controlled inflammation process by DMARDs, we suspected a role of glycerol, petroleum jelly and liquid paraffin mixture (dexeryl®) in melanocyte regeneration. Conclusion: This case would highlight a potential novel indication of glycerol, petroleum jelly and liquid paraffin mixtures (dexeryl®) in vitiligo of autoimmune origin. A clinical trial will be necessary to deeply appreciation this novel therapeutic property of glycerol, petroleum jelly and liquid paraffin mixtures (dexeryl®).

The possible role of Wnt/β-catenin signalling in vitiligo treatment.

Vitiligo is a common chronic skin disease which has an adverse impact on patients' life. Its pathogenesis is complex, involving autoimmunity and oxidative stress (OS). Autoimmunity leads to the loss of epidermal melanocytes and the formation of the depigmented patches of the disease. Treatment of vitiligo should control the exaggerated immune response to arrest the progress of active disease, and then promote melanocytes to repigmentation. Wnt/β-catenin signalling pathway has been of recent interest in vitiligo. Wnt/β-catenin signalling pathway is downregulated in vitiligo. Upregulation of Wnt/β-catenin signalling possibly control vitiligo autoimmune response by protecting melanocyte from OS damage, inhibiting CD8+ T cell effector cell differentiation and enhancing Treg. Wnt/β-catenin signalling plays a critical role in the melanocyte regeneration by driving the differentiation of melanocyte stem cells (McSCs) into melanocytes. Promoting Wnt/β-catenin signalling can not only arrest the progress of active disease of vitiligo but also promote repigmentation. Some of the main effective therapies for vitiligo are likely to work by activating Wnt/β-catenin signalling. Agents that can enhance the effect of Wnt/β-catenin signalling may become potential candidates for the development of new drugs for vitiligo treatment.

Pigment cell progenitor heterogeneity and reiteration of developmental signaling underlie melanocyte regeneration in zebrafish.

Tissue-resident stem and progenitor cells are present in many adult organs, where they are important for organ homeostasis and repair in response to injury. However, the signals that activate these cells and the mechanisms governing how these cells renew or differentiate are highly context-dependent and incompletely understood, particularly in non-hematopoietic tissues. In the skin, melanocyte stem and progenitor cells are responsible for replenishing mature pigmented melanocytes. In mammals, these cells reside in the hair follicle bulge and bulb niches where they are activated during homeostatic hair follicle turnover and following melanocyte destruction, as occurs in vitiligo and other skin hypopigmentation disorders. Recently, we identified melanocyte progenitors in adult zebrafish skin. To elucidate mechanisms governing melanocyte progenitor renewal and differentiation we analyzed individual transcriptomes from thousands of melanocyte lineage cells during the regeneration process. We identified transcriptional signatures for progenitors, deciphered transcriptional changes and intermediate cell states during regeneration, and analyzed cell-cell signaling changes to discover mechanisms governing melanocyte regeneration. We identified KIT signaling via the RAS/MAPK pathway as a regulator of melanocyte progenitor direct differentiation and asymmetric division. Our findings show how activation of different subpopulations of mitfa-positive cells underlies cellular transitions required to properly reconstitute the melanocyte pigmentary system following injury.

Requirement of Zebrafish Adcy3a and Adcy5 in Melanosome Dispersion and Melanocyte Stripe Formation.

cAMP-PKA signaling plays a pivotal role in melanin synthesis and melanosome transport by responding to the binding of the α-melanocyte-stimulating hormone (α-MSH) to melanocortin-1 receptor (MC1R). Adenylate cyclases (ADCYs) are the enzymes responsible for the synthesis of cAMP from ATP, which comprises nine transmembrane isoforms (ADCYs 1-9) and one soluble adenylate cyclase (ADCY 10) in mammals. However, little is known about which and how ADCY isoforms regulate melanocyte generation, melanin biosynthesis, and melanosome transport in vivo. In this study, we have generated a series of single and double mutants of Adcy isoforms in zebrafish. Among them, adcy3a-/- and adcy5-/- double mutants cause defects in melanosome dispersion but do not impair melanoblast differentiation and melanocyte regeneration during the embryonic or larval stages. Activation of PKA, the main effector of cAMP signaling, significantly ameliorates the defects in melanosome dispersion in adcy3a-/- and adcy5-/- double mutants. Mechanistically, Adcy3a and Adcy5 regulate melanosome dispersion by activating kinesin-1 while inhibiting cytoplasmic dynein-1. In adult zebrafish, Adcy3a and Adcy5 participate in the regulation of the expression of microphthalmia transcription factor (Mitfa) and melanin synthesis enzymes Tyr, Dct, and Trp1b. The deletion of Adcy3a and Adcy5 inhibits melanin production and reduces pigmented melanocyte numbers, causing a defect in establishing adult melanocyte stripes. Hence, our studies demonstrate that Adcy3a and Adcy5 play essential but redundant functions in mediating α-MSH-MC1R/cAMP-PKA signaling for regulating melanin synthesis and melanosome dispersion.

Aldh2 is a lineage-specific metabolic gatekeeper in melanocyte stem cells.

ABSTRACTMelanocyte stem cells (McSCs) in zebrafish serve as an on-demand source of melanocytes during growth and regeneration, but metabolic programs associated with their activation and regenerative processes are not well known. Here, using live imaging coupled with scRNA-sequencing, we discovered that, during regeneration, quiescent McSCs activate a dormant embryonic neural crest transcriptional program followed by an aldehyde dehydrogenase (Aldh) 2 metabolic switch to generate progeny. Unexpectedly, although ALDH2 is well known for its aldehyde-clearing mechanisms, we find that, in regenerating McSCs, Aldh2 activity is required to generate formate – the one-carbon (1C) building block for nucleotide biosynthesis – through formaldehyde metabolism. Consequently, we find that disrupting the 1C cycle with low doses of methotrexate causes melanocyte regeneration defects. In the absence of Aldh2, we find that purines are the metabolic end product sufficient for activated McSCs to generate progeny. Together, our work reveals McSCs undergo a two-step cell state transition during regeneration, and that the reaction products of Aldh2 enzymes have tissue-specific stem cell functions that meet metabolic demands in regeneration.

Babchi unani marketed formulation effective in treatment of vitiligo: A case study

Bars (vitiligo) are defined in ancient unani classic as an idiopathic achromia in which skin looses its color. Due to melanocytes deficiency, white spots appeared on body. It may be localized or may spread and become generalized. The disease condition may be stable or some time spread over the body. leucotricha is also sometimes associated with Bars. The achievement of treating this condition in conventional medicines is limited and sometimes, treatment follows with side effects. Though a few case records are documented in the past about the success of various unani medicines. Numerous Unani drugs are well known for the regeneration of melanocytes. The current study was planned to highlight the use of Unani formulation to fight Vitiligo. A 11 year old male have chalky white patches with hypopigmentation without itching over hand, legs, stomach or on back for 1 year, gradually spreading over the chest. The patient was treated with unani oral medication (nobar tablet) and applied ointment, babchi oil locally. After treatment there was repigmentation of skin without any side effect. The treatment modility showed color changes of patches from chalky white to brown and it conclude that unani formulation effective in treatment of vitiligo.

Tfap2b specifies an embryonic melanocyte stem cell that retains adult multifate potential.

SummaryMelanocytes, the pigment-producing cells, are replenished from multiple stem cell niches in adult tissue. Although pigmentation traits are known risk factors for melanoma, we know little about melanocyte stem cell (McSC) populations other than hair follicle McSCs and lack key lineage markers with which to identify McSCs and study their function. Here we find that Tfap2b and a select set of target genes specify an McSC population at the dorsal root ganglia in zebrafish. Functionally, Tfap2b is required for only a few late-stage embryonic melanocytes, and is essential for McSC-dependent melanocyte regeneration. Fate mapping data reveal that tfap2b+ McSCs have multifate potential, and are the cells of origin for large patches of adult melanocytes, two other pigment cell types (iridophores and xanthophores), and nerve-associated cells. Hence, Tfap2b confers McSC identity in early development, distinguishing McSCs from other neural crest and pigment cell lineages, and retains multifate potential in the adult zebrafish.

Tfap2b Specifies an Embryonic Melanocyte Stem Cell That Retains Adult Multi-Fate Potential

Melanocytes, our pigment producing cells, are replenished from multiple stem cell niches in adult tissues. Although pigmentation traits are known risk-factors for melanoma, we know little about melanocyte stem cell (MSC) populations other than hair follicle MSCs, and lack key lineage markers with which to identify MSCs and study their function. Here, we discover that Tfap2b, and a select set of its target genes, specifies an MSC population at the dorsal root ganglia in zebrafish. Functionally, Tfap2b is required for only a few late-stage embryonic melanocytes, and instead is essential for MSC-dependent melanocyte regeneration. Fate-mapping data reveal that tfap2b-expressing MSCs have multi-fate potential, and are the cell-of-origin for large patches of adult melanocytes, and two other pigment cell types, iridophores and xanthophores. Hence, Tfap2b confers MSC identity in early development, thereby distinguishing MSCs from other neural crest and pigment cell lineages, and retains multi-fate potential in the adult zebrafish.

A comprehensive review on vitiligo and its pharmacotherapy: Recent trends and future challenges

Approximately 1% of population in the world is affected by an intriguing skin depigmentation disorder, vitiligo. Typically, a vitiligo lesions are seen as white milky, nonscaly patches with separate edges. Vitiligo is caused by a selective loss of epidermal melanocytes. In vitiligo, there is impaired melanocyte regeneration and/or multiplication. Although the proportion of the population affected by this disease is very low, the disease is associated with a lot of social stigmas. This defect has an important effect on the life of the patient and still a persistent load.

Non-surgical treatment of vitiligo

Vitiligo is an acquired depigmenting skin disorder that affects 0.5% to 2% of the population. Skin lesions from vitiligo, white macules and patches on the skin, can pose a substantial psychological burdencan, causing a significant decrease in one’s quality of life. Recent basic and clinical studies have found that vitiligo is an autoimmune disorder, mediated by CD8+ T-cell and interferon-γ-mediated cytokine/chemokines. Although no treatment modality presents a complete cure for vitiligo, current treatment modalities have a modest effect on vitiligo by reversing the disease’s progression, inducing its stabilization, and promoting melanocyte regeneration. Current non-surgical treatment modalities include topical corticosteroids, topical calcineurin inhibitors, systemic corticosteroids, and phototherapy such as narrowband ultraviolet B phototherapy and excimer laser. In addition, clinicians have used and combined non-surgical treatment modalities based on the activity and extent of vitiligo. Moreover, considering the high risk of vitiligo relapse, maintenance therapy for re-pigmented lesions has also been introduced. Lastly, based on the results of recent translational research, new and emerging treatment modalities have been introduced, such as Janus kinase inhibitors. This review presents an overview of the current non-surgical treatment modalities for vitiligo and discusses emerging treatments.

Maintenance of Melanocyte Stem Cell Quiescence by GABA-A Signaling in Larval Zebrafish.

In larval zebrafish, melanocyte stem cells (MSCs) are quiescent, but can be recruited to regenerate the larval pigment pattern following melanocyte ablation. Through pharmacological experiments, we found that inhibition of γ-aminobutyric acid (GABA)-A receptor function, specifically the GABA-A ρ subtype, induces excessive melanocyte production in larval zebrafish. Conversely, pharmacological activation of GABA-A inhibited melanocyte regeneration. We used clustered regularly interspaced short palindromic repeats/Cas9 to generate two mutant alleles of gabrr1, a subtype of GABA-A receptors. Both alleles exhibited robust melanocyte overproduction, while conditional overexpression of gabrr1 inhibited larval melanocyte regeneration. Our data suggest that gabrr1 signaling is necessary to maintain MSC quiescence and sufficient to reduce, but not eliminate, melanocyte regeneration in larval zebrafish.

Extracellular fraction of adipose tissue as an innovative regenerative approach for vitiligo treatment

Vitiligo is a common, disfiguring autoimmune disease that negatively affects patients' self-esteem and quality of life. Current treatments are moderately effective in reversing disease and promoting melanocyte regeneration. Thus, therapeutic advanced strategies are emerging from regenerative medicine. It has recently emerged that adipose tissue secretome may be used as a cell-free therapy in skin regeneration since paracrine functions of adipose-derived stem cells alone are responsible for most of the therapeutic effect of stem cells in several animal disease models. In this study, we tested the effect of adipose tissue extracellular fraction (AT-Ex) isolated from lipoaspirates on dermal and epidermal vitiligo cells in vitro. Using this experimental model, we demonstrated that molecules secreted by adipose tissue ameliorate the capability to counteract oxidative stress by a physiological stimulation of intracellular antioxidant enzymes and positively impact on cell proliferation. Due to the presence of Wnt-secreted factors, AT-Ex treatment promotes glycogen synthase kinase 3β inactivation and consequently Wnt/β-catenin pathway activation. Collectively, our findings show that AT-Ex could be useful as a natural approach to improve treatment of vitiligo.

Pathogenesis and the emerging Therapy of Vitiligo

Vitiligo is a common and a disfiguring autoimmune disease, which has a negative impact on patients' self-esteem and quality of life. Pathogenesis of Vitiligo involves the interaction between defects of natural and extrinsic melanocytes, immune innate to swelling and destruction of T-cell-mediated melanocyte. Vitiligo affects about 1% of the general population. The risk of the disease was 6% for siblings and 23% for identical twins treatment is not only intended to stop the disease, but also to support repigmentation through the regeneration, proliferation and migration of melanocytes. Treatment strategies for dealing with all aspects of pathogenesis and pigmentation can be very effective, and this strategy may require a combination. Current treatments generally do not imply objective autoimmunity, and emerging treatments may use more specific methods based on a deep understanding of the pathogenesis of the disease, which can provide a good safety profile with a higher effectiveness. However, as with most medical treatments, careful patient selection and monitoring should enable us to normalize the pathogenic response of vitiligo in order to achieve the internal balance of healthy individuals.

Therapeutic management of vitiligo.

Affecting 0.5% of the world's population, vitiligo is an acquired skin disorder that poses major challenges in terms of dermatological care. Characterized by patchy depigmentation, the disease is frequently associated with cosmetic disfigurement and considerable psychological distress. The primary pathophysiological causes for the loss of functional melanocytes are thought to include genetic predisposition, autoimmune mechanisms, and oxidative stress. The present article highlights treatment recommendations contained in the European guidelines as well as those provided by recent reviews on vitiligo. Current therapeutic options are based on three approaches: (1) Regulation of the autoimmune response using topical and systemic immunomodulatory agents (corticosteroids and calcineurin inhibitors); (2) decrease in oxidative stress in melanocytes by means of topical and systemic antioxidants; and (3) activation of melanocyte regeneration using phototherapy (UVB in particular) and transplantation of pigment cells. In addition, patients should be educated in techniques for cosmetic camouflage. Following successful repigmentation, application of calcineurin inhibitors is recommended to prevent recurrences. Combination therapies of the aforementioned approaches are generally considered to be more successful than monotherapies. Early initiation of treatment is associated with a more favorable prognosis. Using the above treatment options, it may be possible to halt disease progression, stabilize depigmented lesions, and achieve repigmentation. Only in exceptional cases should permanent depigmentation be considered as a possible option. New insights into the pathogenesis of vitiligo will likely give rise to novel therapeutic approaches.

Regulation of melanocyte stem cell behavior by the niche microenvironment.

Somatic stem cells are regulated by their niches to maintain tissue homeostasis and repair throughout the lifetime of an organism. An excellent example to study stem cell/niche interactions is provided by the regeneration of melanocytes during the hair cycle and in response to various types of injury. These processes are regulated by neighboring stem cells and multiple signaling pathways, including WNT/β-catenin, KITL/KIT, EDNs/EDNRB, TGF-β/TGF-βR, α-MSH/MC1R, and Notch signaling. In this review, we highlight recent studies that have advanced our understanding of the molecular crosstalk between melanocyte stem cells and their neighboring cells, which collectively form the niche microenvironment, and we focus on the question of how McSCs/niche interactions shape the responses to genotoxic damages and mechanical injury.

Dissecting Wnt Signaling for Melanocyte Regulation during Wound Healing

Abnormal pigmentation is commonly seen in the wound scar. Despite advancements in the research of wound healing, little is known about the repopulation of melanocytes in the healed skin. Previous studies have shown the capacity of melanocyte stem cells in the hair follicle to contribute skin epidermal melanocytes after injury in mice and humans. Here, we focused on the Wnt pathway, known to be a vital regulator of melanocyte stem cells in efforts to better understand the regulation of follicle-derived epidermal melanocytes during wound healing. We showed that transgenic expression of Wnt inhibitor Dkk1 in melanocytes reduced epidermal melanocytes in the wound scar. Conversely, forced activation of Wnt signaling by genetically stabilizing β-catenin in melanocytes increases epidermal melanocytes. Furthermore, we show that deletion of Wntless (Wls), a gene required for Wnt ligand secretion, within epithelial cells results in failure in activating Wnt signaling in adjacent epidermal melanocytes. These results show the essential function of extrinsic Wnt ligands in initiating Wnt signaling in follicle-derived epidermal melanocytes during wound healing. Collectively, our results suggest the potential for Wnt signal regulation to promote melanocyte regeneration and provide a potential molecular window to promote proper melanocyte regeneration after wounding and in conditions such as vitiligo.

210 Mechanistic insight into the repigmentation of piebaldism: Functional characterization of a mutant KIT in melanocyte regeneration

210 Mechanistic insight into the repigmentation of piebaldism: Functional characterization of a mutant KIT in melanocyte regeneration

Repigmentation in vitiligo using the Janus kinase inhibitor tofacitinib may require concomitant light exposure

Vitiligo is an autoimmune disease in which cutaneous depigmentation occurs. Existing therapies are often inadequate. Prior reports have shown benefit of the Janus kinase (JAK) inhibitors. To evaluate the efficacy of the JAK 1/3 inhibitor tofacitinib in the treatment of vitiligo. This is a retrospective case series of 10 consecutive patients with vitiligo treated with tofacitinib. Severity of disease was assessed by body surface area of depigmentation. Ten consecutive patients were treated with tofacitinib. Five patients achieved some repigmentation at sites of either sunlight exposure or low-dose narrowband ultraviolet B phototherapy. Suction blister sampling revealed that the autoimmune response was inhibited during treatment in both responding and nonresponding lesions, suggesting that light rather than immunosuppression was primarily required for melanocyte regeneration. Limitations include the small size of the study population, retrospective nature of the study, and lack of a control group. Treatment of vitiligo with JAK inhibitors appears to require light exposure. In contrast to treatment with phototherapy alone, repigmentation during treatment with JAK inhibitors may require only low-level light. Maintenance of repigmentation may be achieved with JAK inhibitor monotherapy. These results support a model wherein JAK inhibitors suppress T cell mediators of vitiligo and light exposure is necessary for stimulation of melanocyte regeneration.