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Sexual dimorphism in melanocyte stem cell behavior reveals combinational therapeutic strategies for cutaneous repigmentation [RNA-Seq]

ABSTRACT: Vitiligo is an autoimmune skin disease caused by cutaneous melanocyte loss. Although phototherapy and T cell suppression therapy have been widely used to induce epidermal re-pigmentation, full pigmentation recovery is rarely achieved due to our poor understanding of the cellular and molecular mechanisms governing this process. Here, we identify unique melanocyte stem cell (McSC) epidermal migration rates between male and female mice, which is due to sexually dimorphic cutaneous inflammatory responses generated by ultra-violet B exposure. Using genetically engineered mouse models, and unbiased bulk and single-cell mRNA sequencing approaches, we determine that manipulating the inflammatory response through cyclooxygenase and its downstream prostaglandin product regulates McSC proliferation and epidermal migration in response to UVB exposure. Furthermore, we demonstrate that a combinational therapy that manipulates both macrophages and T cells (or innate and adaptive immunity) significantly promotes epidermal melanocyte re-population. With these findings, we propose a novel therapeutic strategy for repigmentation in patients with depigmentation conditions such as vitiligo.

ORGANISM(S): Mus musculus

PROVIDER: GSE247532 | GEO | 2023/12/13

REPOSITORIES: GEO

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Sexual dimorphism in melanocyte stem cell behavior reveals combinational therapeutic strategies for cutaneous repigmentation [scRNA-seq]

Project description:Vitiligo is an autoimmune skin disease caused by cutaneous melanocyte loss. Although phototherapy and T cell suppression therapy have been widely used to induce epidermal re-pigmentation, full pigmentation recovery is rarely achieved due to our poor understanding of the cellular and molecular mechanisms governing this process. Here, we identify unique melanocyte stem cell (McSC) epidermal migration rates between male and female mice, which is due to sexually dimorphic cutaneous inflammatory responses generated by ultra-violet B exposure. Using genetically engineered mouse models, and unbiased bulk and single-cell mRNA sequencing approaches, we determine that manipulating the inflammatory response through cyclooxygenase and its downstream prostaglandin product regulates McSC proliferation and epidermal migration in response to UVB exposure. Furthermore, we demonstrate that a combinational therapy that manipulates both macrophages and T cells (or innate and adaptive immunity) significantly promotes epidermal melanocyte re-population. With these findings, we propose a novel therapeutic strategy for repigmentation in patients with depigmentation conditions such as vitiligo.

2023-12-13 | GSE247694 | GEO

Melanocyte precursors in the hair follicle bulge of repigmented vitiligo skin are controlled by RHO-GTPase, KCTD10 and CTNNB1 signaling

Project description:In repigmentation of human vitiligo, the melanocyte (MC) precursors in the hair follicle (HF) bulge proliferate, migrate and differentiate to repopulate the depigmented epidermis. Here we present a comprehensive characterization of pathways and signals in the bulge that control the repigmentation process. Using biopsies from vitiligo patients we have selectively harvested, by laser capture microdissection, MC and keratinocyte precursors from the HF bulge of untreated vitiligo skin and vitiligo skin treated with Narrow Band UVB (NBUVB). The captured material was subjected to whole transcriptome RNA sequencing. With this strategy, we found that repigmentation in the bulge MCs precursors is driven by KCTD10, a signal with unknown roles in the skin, and by CTNNB1 (encoding β-catenin) and RHO-GTPase (RHO), two signaling pathways previously shown to be involved in pigmentation biology.

2020-11-01 | GSE150954 | GEO

SASH1 S519N variant links skin hyperpigmentation and premature hair graying to dysfunction of melanocyte lineage

Project description:A better understanding of human melanocyte and melanocyte stem cell (McSC) biology is essential for treating melanocyte-related diseases. This study employed an inherited pigmentation disorder carrying the SASH1S519N variant in a Hispanic family to investigate the SASH1 function in melanocyte lineage and the underlying mechanism for this disorder. We used a multidisciplinary approach, including clinical exams, human cell assays, yeast two-hybrid screening, and biochemical techniques. Results linked early hair graying to the SASH1S519N variant, a previously unrecognized clinical phenotype in hyperpigmentation disorders. We identified SASH1 as a novel regulator in McSC maintenance and discovered that TNKS2 is crucial for SASH1’s role in vitro. Additionally, the S519N variant is located in one of multiple tankyrase binding motifs and alters the binding kinetics and affinity of the interaction. In summary, this disorder showcases accelerated aging in human McSC, linking both gain and loss of pigmentation to McSC dysfunction in the same individuals. The findings offer new insights into the roles of SASH1 and TNKS2 in McSC maintenance and the molecular mechanisms of pigmentation disorders. We propose that a comprehensive clinical evaluation of patients with skin disorders should include an assessment and history of hair pigmentation loss.

2024-06-17 | GSE266293 | GEO

Vitiligo non-responding lesions to narrow band UVB have intriguing cellular and molecular abnormalities that may prevent epidermal repigmentation

Project description:We have discovered that human vitiligo patients treated with narrow-band UVB (NBUVB) demonstrated localized resistance to repigmentation in skin sites characterized by distinct cellular and molecular pathways. We used the remaining slides from our immunostaining studies. 1.0 mm2 epidermal scrapes were collected from formalin fixed paraffin embedded (FFPE) transverse sections of biopsies from four paired responding and non-responding vitiligo lesions (8 samples total), following published work (Trejo et al., 2019; Yeakley). The material collected was subjected to whole transcriptome TempO-Seq assay. We used a novel method that combines epidermal scraping and TempO-Seq transcriptome analysis and found that the abnormal environment in non-responding was driven by dysregulated cAMP and WNT/β-catenin signaling pathways. Characterization of abnormal environment that prevents vitiligo repigmentation may open roads for discovery of new drugs that reverse depigmentation.

2024-02-27 | GSE256271 | GEO

Expression data from treatment of human melanocytes with phenolic compounds

Project description:Vitiligo, an acquired disorder characterized by depigmented skin patches, results from loss of epidermal melanocytes. Etiology of vitiligo is not clearly understood but environmental, biochemical, genetic, and immune factors play a role in its pathogenesis. There is evidence that melanocyte death is perpetuated by an autoimmune response that causes lesions to spread. 4-tertiary butyl phenol (4TBP) and monobenzyl ether of hydroquinone (MBEH) are phenolic compounds that are known as environmental causes of vitiligo. We used microarray to detail the global gene expression that occurs following exposure of melanocytes to 4-TBP or MBEH to identified distinct classes of up-regulated genes that may contribute to melanocyte loss in vitiligo. We show that human melanocytes exposed to 4-TBP and MBEH show increased production of some inflammatory cytokines. Interleukin-6 (IL6) and IL8, in particular, are expressed at the periphery of vitiligo lesions and may contribute to recruitment of immune components to the areas, perpetuating melanocyte loss. Cultured human epidermal melanocytes were treated with 4TBP or MBEH for 3, 6, or 24 hours and gene expression were compared with untreated cells.

2012-12-01 | E-GEOD-31641 | biostudies-arrayexpress

Expression data from treatment of human melanocytes with phenolic compounds

2012-12-01 | GSE31641 | GEO

Genome-wide analysis of differential gene expression in human embryonic stem cell-derived central nervous system, neural crest, and progenitor populations over time

Project description:Melanocytes are pigment-producing cells of neural crest origin responsible for protecting the skin against UV-irradiation. Melanocyte dysfunction leads to pigmentation defects including albinism, vitiligo, and piebaldism and is a key feature of systemic pathologies such as Hermansky-Pudlak (HP) and Chediak-Higashi (CH) Syndromes. Pluripotent stem cell technology offers a novel approach for studying human melanocyte development and disease. Here we report that timed exposure to activators of WNT, BMP and EDN3 signaling triggers the sequential induction of neural crest and melanocyte precursor fates under dual-SMAD inhibition conditions. Using a SOX10::GFP hESC reporter line, we demonstrate that the temporal onset of WNT activation is particularly critical for human neural crest induction. Surprisingly, suppression of BMP signaling does reduce neural crest yield. Subsequent differentiation of hESC-derived melanocyte precursors under defined conditions yields pure populations of pigmented cells matching the molecular and functional properties of adult melanocytes. Melanocytes from patient-specific iPSCs faithfully reproduce the ultrastructural features of the HP- and CH-specific pigmentation defects with minimal variability across lines. Our data define a highly specific requirement for WNT signaling during neural crest induction and enable the generation of pure populations of hiPSC-derived melanocytes for faithful modeling of human pigmentation disorders. Total RNA obtained from a timecourse of Dual SMAD Inhibition (DSi), Neural Crest (NC), and Melanocyte (BE) differentiation of human embryonic stem cells in triplicate.

2013-06-01 | E-GEOD-45223 | biostudies-arrayexpress

Genome-wide analysis of gene expression in human pluripotent stem cell-derived melanocyte progenitors, mature melanocytes, and disease-specific melanocytes

Project description:Melanocytes are pigment-producing cells of neural crest origin responsible for protecting the skin against UV-irradiation. Melanocyte dysfunction leads to pigmentation defects including albinism, vitiligo, and piebaldism and is a key feature of systemic pathologies such as Hermansky-Pudlak (HP) and Chediak-Higashi (CH) Syndromes. Pluripotent stem cell technology offers a novel approach for studying human melanocyte development and disease. Here we report that timed exposure to activators of WNT, BMP and EDN3 signaling triggers the sequential induction of neural crest and melanocyte precursor fates under dual-SMAD inhibition conditions. Using a SOX10::GFP hESC reporter line, we demonstrate that the temporal onset of WNT activation is particularly critical for human neural crest induction. Surprisingly, suppression of BMP signaling does reduce neural crest yield. Subsequent differentiation of hESC-derived melanocyte precursors under defined conditions yields pure populations of pigmented cells matching the molecular and functional properties of adult melanocytes. Melanocytes from patient-specific iPSCs faithfully reproduce the ultrastructural features of the HP- and CH-specific pigmentation defects with minimal variability across lines. Our data define a highly specific requirement for WNT signaling during neural crest induction and enable the generation of pure populations of hiPSC-derived melanocytes for faithful modeling of human pigmentation disorders. Total RNA obtained from embryonic stem cells (ESCs), ESC-derived melanocyte progenitors, ESC-derived mature melanocytes, primary melanocytes, and disease-specific induced pluripotent stem cell-derived melanocytes.

2013-06-01 | E-GEOD-45226 | biostudies-arrayexpress

Expression analysis of melanocyte stem cells from Mitfmi-vga9/+ mice reveals a role for MITF in the transcriptional regulation of innate immune gene expression

Project description:Melanocyte stem cells (McSCs) and mouse models of hair graying serve as useful systems to uncover mechanisms involved in stem cell self-renewal and the maintenance of regenerating tissues. Interested in assessing genetic variants of hair graying, we found that the Mitfmi-vga9/+ strain of mice is susceptible to loss of McSC maintenance via ectopic McSC differentiation. Based on transcriptome and molecular analyses of Mitfmi-vga9/+ mice we report a novel role for MITF in the regulation of systemic innate immune gene expression. We also demonstrate that viral mimic (poly I:C) is sufficient to expose genetic susceptibility to hair graying. These observations point to a critical suppressor of innate immunity and the consequences of its dysregulation, and for melanocytes, both may have particular implications for the autoimmune, depigmenting disease vitiligo.

2018-02-04 | GSE102271 | GEO

Phosphodiesterase-4 inhibitors increase pigment cells proliferation and melanization in cultured melanocytes and within a 3D skin equivalent model

Project description:Vitiligo is a common chronic autoimmune disease characterized by white macules and patches of the skin, having a negative impact on patients’ life, and without any definitive cure at present. Identification of new compounds to reverse depigmentation is therefore a pressing need for this disease. The pharmacologic compounds phosphodiesterase-4 inhibitors (PDE4i) are small molecules with immunomodulatory properties, used for treatment of inflammatory dermatoses. PDE4i have shown repigmentation effects in vitiligo patients, in some case reports. We characterized the proliferative and melanogenic potential of two known PDE4i, crisaborole and roflumilast, and of a more recently designed compound, PF-07038124. We used two in vitro model systems, the primary human melanocyte culture and a 3D co-cultured skin model (MelanoDermTM), with an exploratory testing platform composed of complementary assays (spectrophotometry, melanin and proliferation assays, immunostaining, Fontana-Masson staining, qRT-PCR, western blot and whole transcriptome RNA-Sequencing). We identified that the treatment with PDE4i was associated with increased melanocyte proliferation and melanization in both in vitro models, and with increase in the melanogenic genes and proteins expression in cultured melanocytes. These effects were found to be enhanced by addition of a-MSH. In the MelanodermTM tissue, numerous genes and canonical pathways modulated by PDE4i appear to control melanocytic cell function. Our findings support the use of PDE4i with or without a-MSH agonists in vitiligo trials.

2024-09-17 | GSE272551 | GEO

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