ABCG2 deficiency in skin impairs re‐epithelialization in cutaneous wound healing

Abstract

The ATP-binding cassette transporter ABCG2 is expressed in the interfollicular epidermis and mediates the side-population phenotype in skin cells. However, the role of ABCG2 in skin is unclear. Increased expression levels of ABCG2 were found at the basal layer of transitional epidermis adjacent to cutaneous wounds in human patients, indicating that ABCG2 may be involved in regulating the wound healing process. To investigate the role of ABCG2 in cutaneous wound healing, full-thickness skin wounds were created in ABCG2 knockout (ABCG2-KO) and wild-type mice. The healing process was analysed and revealed that ABCG2 deficiency in skin results in delays in wound closure and impairments in re-epithelialization, as evidenced by reductions in both suprabasal differentiation and in p63-expressing keratinocytes migrating from transitional epidermis to epithelial tongues. The reduction in p63-expressing cells may be due to elevated levels of reactive oxygen species in ABCG2-KO epidermis, which can cause DNA damage and lead to proliferation arrest. To determine whether ABCG2 deficiency affects the potency of epidermal stem/progenitor cells (EPCs), transplantation studies were carried out, which demonstrated that ABCG2-KO EPCs display higher levels of γH2AX and lose the capacity to differentiate into suprabasal keratinocytes. A competitive repopulation assay confirmed that ABCG2 expression is critical for the proper expansion and differentiation of EPCs in cutaneous wounds. As EPCs are known to contribute to the healing of larger wounds, the current findings imply a functional role for ABCG2 in the expansion and differentiation of p63-expressing EPCs. Thus, ABCG2 deficiency in skin impairs re-epithelialization in cutaneous wound healing.

Characterization of hair‑follicle side population cells in mouse epidermis and skin tumors

“…Although, lineage studies are necessary to define the relationship between hair follicle and interfollicular SPs, we cannot rule out the possibility that the hair follicle SP might give origin to the interfollicular SP in specific phases of the hair cycle or in pathologic conditions leading to mobilization of the HF keratinocytes to the interfollicular epidermis. This model is supported for a recent publication showing that ABCG2 deficiency in skin impairs re-epithelialization in cutaneous wound-healing ( 49 ). Therefore, it is conceivable that the ABCG2-positive SP plays an active role as progenitors during epidermal regeneration.…”

Actinic lentigines from Japanese and European volunteers share similar impaired biological functions

“…Their function in skin is mainly not described, although some genes, such as ABCG2, CHRNA9 or SLC1A3 may be related to epidermal homeostasis. The transporter ABCG2 is overexpressed in the basal layer of healing skin [38] and its role in stemness and proliferative status of keratinocytes [39] can be linked to other markers of proliferation in AL. Cholinergic receptor α9 (CHRNA9 gene) is involved in the adhesion and motility of keratinocytes at early stages of epidermal morphogenesis [40].…”

Current State of SLC and ABC Transporters in the Skin and Their Relation to Sweat Metabolites and Skin Diseases

“…ABCG2 expression is required for proper expansion and differentiation of epidermal stem cells (reside in a bulge of a hair follicle). ABCG's knockouts resulted in elevated levels of reactive oxygen species and damage DNA leading to proliferation arrest [76].…”