Large scale production of melanocyte derived from pluripotent stem cells for biotherapeutic approaches to treat skin pigmentation disorders
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA922939 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23049418.fastq.gz | Fastqsanger.gz | |||
| SRR23049419.fastq.gz | Fastqsanger.gz | |||
| SRR23049420.fastq.gz | Fastqsanger.gz | |||
| SRR23049421.fastq.gz | Fastqsanger.gz | |||
| SRR23049422.fastq.gz | Fastqsanger.gz |
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Project description:In this study, we successfully defined a highly efficient standardize method to derive hPSCs into a pure population of functional melanocytes. These cells can be maintain for more than 20 passages without observed any senescence. Transcriptomic anlaysis revealed a differentiation process with a logic gene expression profile following the kinetic of melanocyte embryonic development as previously described in mice. Our findings represent a fruitful ground that can serve as a database tool to decipher molecular signatures in normal and pathological conditions
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Project description:BMI1 is required for melanocyte stem cell maintenance and hair pigmentation
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Project description:Waardenburg Syndrome (WS) is a rare genetic disorder that leads to congenital hearing loss and pigmentation defects. MITF is one of its pathogenic genes. While studied extensively in animal models, its pathogenic mechanism still poorly described in humans due to the challenges in accessing embryonic tissues. In recent years, patient-derived human induced pluripotent stem cells(iPSCs) technology offers a promising approach for modeling human melanocyte development and hereditary disease. In this work, we make use of iPSCs derived from one WS patient carrying a heterozygous mutation in MITF gene. Accordingly, we establish a pipeline for profiling iPSCs during differentiation toward the melanocyte, which can be used to characterize the differentiation properties of the MITF+/- melanocytes. The MITF+/- cell lines showed a reduction in expression of the characteristic melanocyte-related gene expression profile. Analysis of the melanosome maturation process by electron microscopy revealed a lower percentage of mature, fully pigmented melanosomes. Compare with the WT cell lines, The transcriptome analysis reveals widespread gene expression changes at the stage of melanocyte in MITF+/- cell lines, and the differentially expressed genes(DEGs) were enriched with gene ontology (GO) of melanogenesis related pathway. Interesting, ion transport-related genes were also shown significantly difference in MITF+/- induced melanocyte, indicating the mutant MITF may lead to the dysfunction of potassium channels and transporters produced by intermediate cells in cochlear, further causes phenotypes of deafness. Altogether, our study provide valuable insights into how reduced MITF expression in WS patients might resulting in defective melanocyte development and related phenotype base on the patient-derived hiPSC model. The possibility of integrating laboratory data with clinical phenotypes will bring us toward precision medicine approaches in WS in the future.
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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
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.
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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.
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Project description:The epigenetic repressor BMI1 plays an integral role in promoting the self-renewal and proliferation of many adult stem cell populations, and also tumor types, primarily through silencing the Cdkn2a locus, which encodes the tumor suppressors p16Ink4a and p19Arf. However, in cutaneous melanoma, BMI1 drives epithelial-mesenchymal transition programs, and thus metastasis, while having little impact on proliferation or primary tumor growth. This raised questions about the requirement and role for BMI1 in melanocyte stem cell (MeSC) biology. Here, we demonstrate that murine melanocyte-specific Bmi1 deletion causes premature hair greying, which results from gradual MeSC loss. We establish that MeSC loss begins in the second hair cycle and is accompanied by melanocyte depletion. RNA-seq of MeSCs revealed that Bmi1 deletion induces transcriptional upregulation of p16Ink4a and p19Arf, mirroring the central role of BMI1 in other stem cell contexts. Additionally, the glutathione S-transferase enzymes Gsta1 and Gsta2 are downregulated by BMI1 loss, raising the possibility that MeSCs could be susceptible to oxidative stress. Accordingly, treatment with the antioxidant N-acetyl cysteine (NAC) partially rescued melanocyte expansion. Together, our data establish a critical role for BMI1 in MeSC maintenance that reflect a partial role for suppression of oxidative stress, and likely transcriptional repression of Cdkn2a.
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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.
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Project description:Feather coloration is one of the most extraordinary examples of phenotypic diversity. This diversity results both from the variation in hue as well as from the presence/absence of pigment in distinct feather regions. The mechanisms that drive presence/absence of pigmentation in feathers are not yet fully understood. Here we characterize the gene expression profiles associated with differential melanin pigmentation in Dark-eyed junco (Junco hyemalis) tails, a social feather ornament used in courtship and male-male competition. Junco tail feathers contain both white apigmented regions as well as dark melanin-pigmented regions. We compared the transcriptome-wide gene expression in developing white and dark regions of tail feathers to understand the regulatory pathways that may regulate the development of this feather ornament. We show that both white and dark feathers express melanocyte markers, indicating that white feathers contain cells capable of producing pigment. However, only dark cells express genes associated with melanin synthesis. We identify differences in expression of genes that may regulate melanocyte activation in dark feathers. Future studies should experimentally test the role of these genes in driving differences in feather pigmentation.
2023-01-08 | GSE167085 | GEO
Project description:Lineage-specific differentiation programs are activated by epigenetic changes in chromatin structure. Melanin-producing melanocytes maintain a gene expression program ensuring appropriate enzymatic conversion of metabolites into the pigment, melanin, and its transfer to surrounding cells. During neuroectodermal development, SMARCA4, the catalytic subunit of SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes, is essential for lineage specification. SMARCA4 is also required for development of multipotent neural crest precursors into melanoblasts, which differentiate into pigment-producing melanocytes. In addition to the catalytic domain, SMARCA4 and several SWI/SNF subunits contain bromodomains which are amenable to pharmacological inhibition. We investigated the effects of pharmacological inhibitors of SWI/SNF bromodomains on melanocyte differentiation. Strikingly, treatment of murine melanoblasts and human neonatal epidermal melanocytes with selected bromodomain inhibitors abrogated melanin synthesis and visible pigmentation. Using functional genomics, iBRD9, a small molecule selective for the bromodomain of BRD9, repressed pigmentation-specific gene expression. Depletion of BRD9 confirmed a requirement for expression of pigmentation genes in the differentiation program from melanoblasts into pigmented melanocytes and in melanoma cells. Chromatin immunoprecipitation assays showed that iBRD9 disrupts the occupancy of bromodomain containing 9 (BRD9) and the catalytic subunit SMARCA4. These data indicate that BRD9 promotes melanocyte differentiation and pigmentation whereas pharmacological inhibition of BRD9 is repressive.
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