Regeneration of collagen fibrils at the papillary dermis by reconstructing basement membrane at the dermal-epidermal junction.

The epidermal basement membrane deteriorates with aging. We previously reported that basement membrane reconstruction not only serves to maintain epidermal stem/progenitor cells in the epidermis, but also increases collagen fibrils in the papillary dermis. Here, we investigated the mechanism of the latter action.

Basement Membrane Helps Maintain Epidermal Hyaluronan Content.

Hyaluronan (HA) is the major glycosaminoglycan in the extracellular matrix of most mammalian tissues, including the epidermis. It is synthesized in epidermis, and mainly metabolized after transfer to the liver via lymphatic vessels in the dermis following its passage through the basement membrane (BM) at the dermal-epidermal junction. The aim of the present study was to investigate the influence of BM integrity on the level of HA in the epidermis.

Decrease of laminin-511 in the basement membrane due to photoaging reduces epidermal stem/progenitor cells.

Daily sunlight exposure damages the epidermal basement membrane (BM) and disrupts epidermal homeostasis. Inter-follicular epidermal stem cells (IFE-SCs) regulate epidermal proliferation and differentiation, which supports epidermal homeostasis. Here, we examine how photoaging affects the function of IFE-SCs and we identify key components in their cellular environment (niche).

1-(2-Hydroxyethyl)-2-imidazolidinone, a heparanase and matrix metalloproteinase inhibitor, improves epidermal basement membrane structure and epidermal barrier function.

Daily exposure to sunlight is known to affect the structure and function of the epidermal basement membrane (BM), as well as epidermal differentiation and epidermal barrier function. The aim of this study is to clarify whether the inhibition of BM-degrading enzymes such as heparanase and matrix metalloproteinase 9 (MMP-9) can improve the epidermal barrier function of facial skin, which is exposed to the sun on a daily basis. 1-(2-hydroxyethyl)-2-imidazolidinone (HEI) was synthesized as an inhibitor of both heparanase and MMP-9.

Smad7 Ameliorates TGF-β-Mediated Skin Inflammation and Associated Wound Healing Defects but Not Susceptibility to Experimental Skin Carcinogenesis.

We assessed the roles of Smad7 in skin inflammation and wound healing using genetic and pharmacological approaches. In K5.TGFβ1/K5.

Hyperpigmentation in human solar lentigo is promoted by heparanase-induced loss of heparan sulfate chains at the dermal-epidermal junction.

Background: Skin pigmentation induced by ultraviolet B radiation is caused in part by inflammation mediated by cytokines secreted from keratinocytes and fibroblasts in the irradiated area. Heparanase is also activated in the irradiated skin, and this leads to loss of heparan sulfate at the dermal-epidermal junction (DEJ), resulting in uncontrolled diffusion of heparan sulfate-binding cytokines through the DEJ. However, it is not clear whether heparanase-induced loss of heparan sulfate at the DEJ is involved in the pigmentation process in sun-exposed skin.

Key role of heparan sulfate chains in assembly of anchoring complex at the dermal-epidermal junction.

Epidermal basement membrane forms anchoring complex composed of hemidesmosomes, anchoring filaments, lamina densa and anchoring fibrils to link epidermis to dermis. However, the anchoring complex is rarely formed in skin equivalent models, probably because of degradation of extracellular matrix (ECM) proteins and heparan sulfate chains by matrix metalloproteinases (MMPs) and heparanase, respectively. To explore the roles of ECM proteins and heparan sulfate in anchoring complex assembly, we used specific inhibitors of MMPs and heparanase, and the formation of anchoring complex was analysed in terms of polarized deposition of collagen VII, BP180 and β4 integrin at the dermal-epidermal junction (DEJ) by means of immunohistochemistry and transmission electron microscopy (TEM).

Influence of heparan sulfate chains in proteoglycan at the dermal-epidermal junction on epidermal homeostasis.

Basement membrane (BM) plays important roles in skin morphogenesis and homeostasis by controlling dermal-epidermal interactions. However, it remains unclear whether heparan sulfate (HS) chains of proteoglycan in epidermal BM contribute to epidermal homeostasis. To explore the function of HS chains at the dermal-epidermal junction (DEJ), we used a skin equivalent (SE) model.

Activation of heparanase by ultraviolet B irradiation leads to functional loss of basement membrane at the dermal-epidermal junction in human skin.

Recently, we reported that heparanase plays important roles in barrier-disrupted skin, leading to increased interaction of growth factors between epidermis and dermis and facilitating various cutaneous changes, including epidermal hyperplasia and wrinkle formation. However, the role of heparanase in sun-exposed skin remains unknown. Here, we show that heparanase in human keratinocytes is activated by ultraviolet B (UVB) exposure and that heparan sulfate of perlecan is markedly degraded in UVB-irradiated human skin.

Heparanase activation induces epidermal hyperplasia, angiogenesis, lymphangiogenesis and wrinkles.

To clarify the difference between cutaneous responses to single and repeated barrier disruption, changes of epidermal gene expression were examined by using RT-PCR. In repeatedly barrier-disrupted skin, heparanase was specifically up-regulated in epidermis. In addition, there was a marked decrease in heparan sulfate (HS) chains of perlecan in basement membrane at the dermal-epidermal junction (DEJ) compared with singly disrupted skin.

Fibulin-5 accelerates elastic fibre assembly in human skin fibroblasts.

Fibulin-5 null mice display abnormalities in the elastic fibres in the dermis. We postulated, therefore, that fibulin-5 might be a regulator of elastic fibre assembly and stability. To clarify the role of fibulin-5 in elastic fibre formation, we employed in vitro systems that allowed increasing expression of elastic fibre components by gene transduction using retroviral vector constructs.

Hair follicle regeneration using grafted rodent and human cells.

Hair follicle regeneration involves epithelial-mesenchymal interactions (EMIs) of follicular epithelial and dermal papilla (DP) cells. Co-grafting of those cellular components from mice allows complete hair reconstitution. However, regeneration of human hair in a similar manner has not been reported.

Chemical peeling by SA-PEG remodels photo-damaged skin: suppressing p53 expression and normalizing keratinocyte differentiation.

Chemical peeling with salicylic acid in polyethylene glycol vehicle (SA-PEG), which specifically acts on the stratum corneum, suppresses the development of skin tumors in UVB-irradiated hairless mice. To elucidate the mechanism through which chemical peeling with SA-PEG suppresses skin tumor development, the effects of chemical peeling on photodamaged keratinocytes and cornified envelopes (CEs) were evaluated in vivo. Among UVB-irradiated hairless mice, the structural atypia and expression of p53 protein in keratinocytes induced by UVB irradiation were intensely suppressed in the SA-PEG-treated mice 28 days after the start of weekly SA-PEG treatments when compared to that in the control UVB-irradiated mice.