Abstract
Epidermis, a continuously self-renewing and differentiating organ, produces a protective stratum corneum that shields us from external chemical, physical and microbial threats. Epidermal differentiation is a multi-step process regulated by influences, some unknown, others insufficiently explored. Detachment of keratinocytes from the basement membrane is one such pro-differentiation stimulus. Here, we define the transcriptional changes during differentiation, especially those caused by detachment from the substratum. Using comprehensive transcriptional profiling, we revisited the effects of detachment as a differentiation signal to keratinocytes. We identified the genes regulated by detachment, the corresponding ontological categories and, using metaanalysis, compared the genes and categories to those regulated by other pro-differentiating stimuli. We identified 762 genes overexpressed in suspended keratinocyte, including known and novel differentiation markers, and 1427 in attached cells, including basal layer markers. Detachment induced epidermis development, cornification and desmosomal genes, but also innate immunity, proliferation inhibitors, transcription regulators and MAPKs; conversely the attached cells overexpressed cell cycle, anchoring, motility, splicing and mitochondrial genes, and both positive and negative regulators of apoptosis. Metaanalysis identified which detachment-regulated categories overlap with those induced by suprabasal location in vivo, by reaching confluency in vitro, and by inhibition of JUN kinases. Attached and in vivo basal cells shared overexpression of mitochondrial components. Interestingly, melanosome trafficking components were also overexpressed in the attached and in vivo basal keratinocytes. These results suggest that specific pro-differentiation signals induce specific features of the keratinization process, which are in vivo orchestrated into harmonious epidermal homeostasis.
Highlights
Human epidermis is a constantly self-renewing and differentiating structure, composed mainly of keratinocytes that proliferate in the basal layer and, after detachment, progress through a complex process that results in a protective stratum corneum
In a pioneering study a decade-and-half ago Dr Watt and her collaborators suggested that the detachment from the basement membrane is one of stimuli for differentiation; they showed that keratinocytes, prevented from attachment to a substratum, produce involucrin a canonical differentiation marker [11]
When we compared the confluency-induced changes in keratinocytes grown in the presence or absence of EGF [17], we find virtually identical effects, except that apoptosis is induced in the absence, but not in the presence of EGF
Summary
Human epidermis is a constantly self-renewing and differentiating structure, composed mainly of keratinocytes that proliferate in the basal layer and, after detachment, progress through a complex process that results in a protective stratum corneum. In a pioneering study a decade-and-half ago Dr Watt and her collaborators suggested that the detachment from the basement membrane is one of stimuli for differentiation; they showed that keratinocytes, prevented from attachment to a substratum, produce involucrin a canonical differentiation marker [11]. They demonstrated that fibronectin can partially delay this process, and so can laminin and collagen [12]. These components of the basement membrane are all ligands for integrins, which suggested that integrin signaling, or rather lack thereof, plays a role in initiating keratinocyte differentiation [13,14]
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