Abstract
In vitiligo, chronic loss of melanocytes and consequent absence of melanin from the epidermis presents a challenge for long-term tissue maintenance. The stable vitiligo patches are known to attain an irreversible depigmented state. However, the molecular and cellular processes resulting in this remodeled tissue homeostasis is unclear. To investigate the complex interplay of inductive signals and cell intrinsic factors that support the new acquired state, we compared the matched lesional and non-lesional epidermis obtained from stable non-segmental vitiligo subjects. Hierarchical clustering of genome-wide expression of transcripts surprisingly segregated lesional and non-lesional samples in two distinct clades, despite the apparent heterogeneity in the lesions of different vitiligo subjects. Pathway enrichment showed the expected downregulation of melanogenic pathway and a significant downregulation of cornification and keratinocyte differentiation processes. These perturbations could indeed be recapitulated in the lesional epidermal tissue, including blunting of rete-ridges, thickening of stratum corneum and increase in the size of corneocytes. In addition, we identify marked increase in the putrescine levels due to the elevated expression of spermine/spermidine acetyl transferase. Our study provides insights into the intrinsic self-renewing ability of damaged lesional tissue to restore epidermal functionality in vitiligo.
Highlights
In vitiligo, chronic loss of melanocytes and consequent absence of melanin from the epidermis presents a challenge for long-term tissue maintenance
As the levels of PUT are elevated in the total epidermis of vitiligo lesions, we propose that these are localized to the stratum corneum layer and contribute to the alterations observed in the histological sections
While the apparent downregulation of genes involved in melanogenesis is anticipated owing to the loss of melanocytes, alteration in keratinocyte-specific process is non-intuitive
Summary
Chronic loss of melanocytes and consequent absence of melanin from the epidermis presents a challenge for long-term tissue maintenance. The lesional skin from vitiligo subjects is characterized by the conspicuous absence of the pigment producing cells, melanocytes. Within these cells, melanin pigment is synthesized and deposited in specialized organelles called melanosomes, which are transferred to the neighboring keratinocytes, constituting the minimal functional epidermal melanin unit in the human skin[1]. Previous genome-wide expression studies on intact biopsies from lesional and non-lesional skin compared to healthy controls indicated a functional role of natural killer cells and autoimmunity in melanocyte loss[18]. Comparison of transcriptome between melanocyte cultures from the asymptomatic non-lesional vitiligo skin with healthy donors showed differential expression of genes involved in the regulation of melanosome maturation and antigen presentation, providing valuable insights into disease pathomechanisms[19]. Pair-wise analysis reduced the heterogeneity, which enabled us to comprehensively delineate vitiligo-specific perturbations in the skin, as a consequence of the melanocyte loss
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