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Fibroblast-directed melanocyte recruitment via Cxcl12-Cxcr4 cascade promotes post-inflammatory hyperpigmentation and skin barrier protection in zebrafish

ABSTRACT: Post-inflammatory hyperpigmentation (PIH) is a common skin disorder characterized by brown or black macules. It can be categorized as transient, typically resolving within 6–12 months, or permanent, persisting for years. While the pathogenesis of PIH is commonly linked to localized melanocyte overactivation, the precise cellular and molecular basis for this dysregulation, as well as its physiological significance, remains poorly defined. Using an acetic acid-induced zebrafish model, we identify melanocyte migration as a critical driver of hyperpigmentation. This process is independent of immune cells but driven by fibroblasts, which secrete Cxcl12a to recruit melanocytes via the Cxcl12a–Cxcr4a axis. Fibroblast ablation irreversibly disrupts melanocyte patterning, indicating that aberrant fibroblast activity dictates the permanence of PIH. The recruited melanocytes form a dual protective barrier against both UV-induced DNA damage and microbial intrusion. The translational relevance of this mechanism is underscored by upregulated CXCL12 expression in fibroblasts from human PIH-related conditions such as keloids, acne, and atopic dermatitis. Therapeutically, the FDA-approved CXCR4 antagonist AMD3100 (Plerixafor) effectively prevents and treats PIH in our model. Our findings elucidate a fibroblast-mediated mechanism of melanocyte recruitment in PIH, uncover previously unappreciated barrier functions of melanocytes in skin repair, and propose a promising repurposed treatment strategy.

ORGANISM(S): Danio rerio

PROVIDER: GSE302529 | GEO | 2025/10/01

REPOSITORIES: GEO

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Project description:Depolarization of resting membrane potential in select cells in Xenopus larvae induces striking hyperpigmentation due to dysregulation of melanocytes. Here, we show that this non-cell-autonomous process is mediated by cAMP, CREB, and the transcription factors Sox10 and Slug. Our microarray analysis reveals specific transcripts responsive to Vmem levels within a few hours of depolarization, and a set of 517 transcripts whose expression remains altered during the full hyperpigmented phenotype over a week later, linking instructor cell-depolarization to a range of developmental processes and disease states. We also show that voltage-dependent conversion of melanocytes involves the MSH-secreting melanotrope cells of the pituitary, and formulate a model for the molecular pathway linking the bioelectric properties of melanocyte cellsâ microenvironment in vivo to the genetic and cellular changes induced in this melanoma-like phenotype. Remarkably, the phenotype is all-or-none: each individual animal either undergoes melanocyte conversion or not, as a whole. This group decision is stochastic, resulting in varying percentages of hyperpigmented individuals for a given experimental treatment. To understand the stochasticity and dynamic properties of this complex signaling system, we developed a novel computational method that automates the reverse-engineering of stochastic dynamic signaling models. We used this method to discover a network model that quantitatively explained our complex dataset, and even made correct predictions for new experiments that we validated in vivo. Taken together, these data (1) reveal new molecular details about a novel trigger of metastatic-like developmental cell behavior in vivo, (2) suggest new targets for biomedical intervention, and (3) demonstrate proof-of-principle of a computational method for understanding stochastic decision-making by cells during embryonic development and metastasis. Gene expression analysis was performed using samples treated with ivermectin from NF stage 10 onwards, collected at two developmental stages; stage 15 (early neurula) and stage 45 (free-swimming tadpole). Embryos were collected in eppendorf tubes (N=50 for stage 15, N=5 for stage 45) and frozen at -80Â°C. RNA extraction and microarray analysis were performed by the Beth Israel Deaconess Medical Center Genomics and Proteomics Center (Harvard) according to standard Affymetrix protocol, using a high throughput hybridization and scanning system. Microarray hybridization was performed using the Affy 3â IVT Express Kit. Fragmented and biotin labeled and amplified RNA was hybridized to the GeneChipÂ® Xenopus laevis Genome 2.0 array as per manufacturerâs protocol. The Affymetrix GeneChipÂ® X. laevis Genome 2.0 Array, has 32,400 probe sets representing more than 29,900 X. laevis transcripts.

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Fibroblast-directed melanocyte recruitment via Cxcl12-Cxcr4 cascade promotes post-inflammatory hyperpigmentation and skin barrier protection in zebrafish

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