Mapping architectural and transcriptional alterations in non-lesional and lesional epidermis in vitiligo

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.

Involvement of non‐melanocytic skin cells in vitiligo

“…Interestingly, acanthosis occurs also in normal‐appearing skin . In line with histological findings, vitiligo‐specific traits have been identified at architectural, cellular and transcriptomic levels, revealing alteration in the processes of keratinocyte differentiation and cornification in lesional epidermis …”

“…Secreted Wnt ligands are necessary for the delay of senescence since repression of Wnt pathway is an early signal for cell senescence onset . Consequently, due to the association with inflammation, cellular stress and senescence and the modulation of DKK1 expression, or of the downstream Wnt signalling, represent a possible therapeutic target for vitiligo …”

The convergence theory for vitiligo: A reappraisal

“…Although melanosome transfer remains poorly understood, it is clear that both cell types are required for skin pigmentation . Thus, morphologic aberrancies in keratinocytes from patient skin, which extend well beyond the lesional area, are relevant to the disease process . A better understanding of such abnormalities is needed .…”

“…Although suggestive of an aetiologic contribution for keratinocytes in vitiligo, most work has focused on the limited ability of lesional keratinocytes to support repigmentation. Reduced differentiation by lesional keratinocytes is a hallmark of vitiligo . Compared to non‐lesional skin, blisters generated from lesional skin contain a greater number of apoptotic keratinocytes, indicating a possible history of trauma .…”

Lesional skin in vitiligo exhibits delayed in vivo reepithelialization compared to the nonlesional skin

“…Under identical conditions, keratinocytes derived from lesional epidermis can be cultured for a lesser number of passages compared to paired nonlesional skin . Further, a significantly thickened stratum corneum, along with elevated levels of the polyamine putrescene and a distinct transcriptional signature (altered SCF‐cKIT network and oxidative stress pathway) have also been reported in the lesional epidermis …”