[Differences in anatomical area-specific wound healing in hidradenitis suppurativa/acne inversa after surgery].

BACKGROUND: Hidradenitis suppurativa/acne inversa is an inflammatory, debilitating disease for which wide local excision of the affected area with secondary wound healing is considered the treatment of first choice for the inactive scarring form or after adequate anti-inflammatory medical treatment. OBJECTIVES: In this study, we aimed to assess the duration of complete secondary wound healing after surgical intervention for hidradenitis suppurativa/acne inversa. MATERIALS & METHODS: Twenty-three surgical procedures in 17 consecutive patients (eight female, nine male) were evaluated for duration of secondary wound healing at axillary or anogenital/inguinal sites. To investigate the contribution of hair follicle bulge progenitor cells in wound re-epithelialization, tissue samples of lesional and perilesional skin were analysed for expression of the stem cell marker, cytokeratin 15 (CK15), and CD200, a marker for human follicular stem cells that resides in the bulge area. RESULTS: Initial wound size did not differ significantly between surgical wounds in the axillary (mean: 30.0 cm2 ± 5.4) and anogenital/inguinal (mean: 35.3 cm2 ± 5.7) region. However, healing time to complete wound closure was almost twice as fast in the anogenital/inguinal (mean: 132 days ± 10.4) than axilla area (mean: 254 days ± 39.1; p < 0.01). The accelerated wound healing in the anogenital/inguinal region was accompanied by significantly enhanced CK15 and CD200 expression, compared to axillary wounds (p < 0.05). CONCLUSION: The anogenital/inguinal region showed significantly faster secondary wound healing after surgical intervention for hidradenitis suppurativa/acne inversa compared to axillary wounds. We suspect differences in pilosebaceous unit density and thus hair follicle progenitor cells (as mirrored by CK15 and CD200 expression) to be the main driver behind this finding.

A keratin 15 containing stem cell population from the hair follicle contributes to squamous papilloma development in the mouse.

The multistage model of nonmelanoma skin carcinogenesis has contributed significantly to our understanding of epithelial cancer in general. We used the Krt1-15CrePR1;R26R transgenic mouse to determine the contribution of keratin 15+ cells from the hair follicle to skin tumor development by following the labeled progeny of the keratin 15 expressing cells into papillomas. We present three novel observations. First, we found that keratin 15 expressing cells contribute to most of the papillomas by 20 weeks of promotion. Second, in contrast to the transient behavior of labeled keratin 15-derived progeny in skin wound healing, keratin 15 progeny persist in papillomas, and some malignancies for many months following transient induction of the reporter gene. Third, papillomas have surprising heterogeneity not only in their cellular composition, but also in their expression of the codon 61 signature Ha-ras mutation with approximately 30% of keratin 15-derived regions expressing the mutation. Together, these results demonstrate that keratin 15 expressing cells of the hair follicle contribute to cutaneous papillomas with long term persistence and a subset of which express the Ha-ras signature mutation characteristic of initiated cells.

Progeny of Lgr5-expressing hair follicle stem cell contributes to papillomavirus-induced tumor development in epidermis.

Epidermal keratinocytes and hair follicle (HF) stem cells (SCs) expressing oncogenes are competent at developing squamous cell carcinomas (SCCs) in epidermis and HFs, respectively. To determine whether bulge and hair germ (HG) SCs from HF contribute to SCC generation at distant epidermis, the most frequent epidermal region where these lesions arise in human skin, we used a skin cancer mouse model expressing E6 and E7 oncoproteins from Human papillomavirus (HPV) 16 in SCs and basal keratinocytes. This previously described mouse model recapitulates the human skin papillomavirus-induced SCC pathology. We show that E6 and E7 expression promote the expansion of keratin 15 (K15)-expressing cells. These K15(+) aberrant cells exhibit some HGSC markers and diminished expression of Tcf3 and Sox9 hair SC specification genes, which are accumulated in HFs and mislocalized to interfollicular epidermis. Leucine-rich G-protein-coupled receptor 5 (Lgr5)-expressing SCs, localized in the bulge and HG, are the origin of the expanded K15(+) cell population. A large subset of the Lgr5(+) SC progeny, expressing K15 and P-cadherin, is aberrantly mobilized to the upper region of HFs and the epidermis, and accumulates at E6/E7-induced pre-neoplastic lesions and epidermal tumors. These findings indicate that aberrant accumulation of altered SCs in HFs and their subsequent migration to the epidermis contribute to HPV-induced tumor development.

Cytokeratin15-positive basal epithelial cells targeted in graft-versus-host disease express a constitutive antiapoptotic phenotype.

The normal gene expression profile of rete-tip keratinocytes targeted in human graft-versus-host disease (GVHD) remains unexplored. Murine lingual epithelium, unlike murine skin, consists of a basal layer that resembles human cutaneous rete ridges and harbors rete tip-associated cells that express cytokeratin 15 (K15), a marker for epithelial stem cells. Target cell apoptosis in murine GVHD preferentially involves subpopulations of basal cells that (1) reside at tips of lingual rete ridge-like prominences (RLPs), (2) constitutively express K15 protein, (3) express the proapoptotic protein Bax early in disease progression, and (4) coincide spatially with putative epithelial stem cells. Here, we show by real-time reverse transcription-PCR that immunohistochemistry-guided laser-captured K15-positive (K15+) murine basal cells constitutively express quantitatively higher mRNA levels for K15 but lower mRNA levels of Bax than do K15- basal cells, consistent with the presumed stem cell nature of K15+ basal cells. Moreover, apoptosis gene array screening of K15+ microdissected basal cells demonstrated a dominant trend toward the preferential expression of genes associated with protection from apoptosis. Accordingly, genes that regulate apoptotic vulnerability are differentially expressed in basal layer subpopulations distinguishable by K15 expression.