Abstract
The well documented decline in the regenerative ability of ageing human skin has been attributed to many factors including genomic instability, telomere shortening, poor nutrient sensing, cellular senescence, and stem cell exhaustion. However, a role for the dermal cellular and molecular microenvironment in skin ageing is just emerging. We previously showed that dermal pericytes co-operate with fibroblasts to improve human skin regeneration in an organotypic skin culture model, and even do so in the absence of fibroblasts. Here, we report that the number of dermal cells, particularly pericytes, declines significantly in human skin of donors aged > 50 years. Notably, aged pericytes promoted epidermal regeneration of neonatal keratinocytes in organotypic cultures and the resulting epithelium exhibited a Ki67+/ΔNp63+ basal layer and terminal differentiation. However, the epithelium lacked several features of homeostasis displaying lower levels of ΔNp63 expression, decreased LAMA5 deposition at the dermo-epidermal junction, and the absence of basement membrane and hemi-desmosome assembly. We conclude that a decline in pericyte incidence and function contribute to an impaired epidermal microenvironment and poor skin regeneration with ageing in the human skin.
Highlights
It is well accepted that the dermis acts as a niche for the interfollicular and hair follicle epidermis of the skin, mediated by an array of extracellular matrix (ECM) proteins and growth factors [1]
A significant decrease in pericyte numbers was observed in skin samples from donors aged over 50 years compared to skin from 17–30 yo and 31–40 yo donors (Figure 1E, left panel; 9 random fields from each of 3 donors per age group, p < 0.001), when expressed as the number of PDGFRβ+ pericytes/dermal area
Given that keratinocytes from aged human skin exhibit poor regenerative ability both in vitro and in vivo [15,34,35], we asked whether this may be partially due to degenerative changes in the dermal microenvironment with ageing, both qualitatively or quantitatively
Summary
It is well accepted that the dermis acts as a niche for the interfollicular and hair follicle epidermis of the skin, mediated by an array of extracellular matrix (ECM) proteins and growth factors [1]. Changes in mechanical stress and cell density act as signals for cell replacement in development and homeostasis [2,3]. The role of dermal fibroblasts in promoting epidermal cell proliferation and differentiation ex-vivo in both 2D [15] and 3D OC models [16] was clearly demonstrated by the absolute dependence of epidermal cells on dermally secreted factors, including ECM proteins, e.g., collagens, laminins, and proteoglycans, and paracrine growth factors. Attempts to identify functionally relevant fibroblast subsets that promote epidermal regeneration during development, wound repair, and homeostasis have been undertaken based on physical location, lineage mapping, and RNA seq analysis [17,18,19,20,21,22,23,24]
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