Regeneration of Collagen Fibrils at the Papillary Dermis by Reconstructing Basement Membrane at the Dermal-Epidermal Junction

Abstract

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 fibers in the papillary dermis. Here, we investigated the mechanism of the latter action. Collagen fibrils in the papillary dermis were increased in organotypic human skin culture treated with matrix metalloproteinase and heparinase inhibitors. The expression levels of COL5A1 and COL1A1 genes (encoding collagen type V α 1 chain and collagen type I α 1 chain, respectively) were increased in fibroblasts cultured with conditioned medium from a skin equivalent model cultured with the inhibitors and in keratinocytes cultured on laminin-511 fragment-coated plates. We then examined cytokine expression, and found that the inhibitors increased the expression of PDGF-BB (platelet-derived growth factor consisting of two B subunits) in epidermis. Expression of COL5A1 and COL1A1 genes was increased in cultured fibroblasts stimulated with PDGF-BB. Further, the bifunctional inhibitor hydroxyethyl imidazolidinone (HEI) increased skin elasticity and the thickness of the papillary dermis in the skin equivalent. Taken together, our data suggests that reconstructing the basement membrane promotes secretion of PDGF-BB by epidermal keratinocytes, leading to increased collagen expression at the papillary dermis.

Skin aging from mechanisms to interventions: focusing on dermal aging

“…It has been postulated that disrupted basement membranes allow soluble melanogenic regulators from senescent fibroblasts to more easily stimulate melanocyte activity and accelerate age-related pigmentation (Goyarts et al, 2007;Amano, 2009;Iriyama et al, 2011b;Bastonini et al, 2016). Iriyama et al (2022) have shown that the inhibition of basement membrane degradation with MMP inhibitors and heparinase inhibitors promotes the deposition of laminin-511 at the DEJ, which in turn promotes the secretion of platelet-derived growth factor consisting of 2 B subunits (PDGF-BB). Expression of COL5A1 and COL1A1 genes was increased in the fibroblasts stimulated with PDGF-BB, suggesting increased collagen expression in the papillary dermis (Iriyama et al, 2022).…”

“…Iriyama et al (2022) have shown that the inhibition of basement membrane degradation with MMP inhibitors and heparinase inhibitors promotes the deposition of laminin-511 at the DEJ, which in turn promotes the secretion of platelet-derived growth factor consisting of 2 B subunits (PDGF-BB). Expression of COL5A1 and COL1A1 genes was increased in the fibroblasts stimulated with PDGF-BB, suggesting increased collagen expression in the papillary dermis (Iriyama et al, 2022). Therefore, strengthening the damaged basement membrane and restoring epidermaldermal integrity have been proposed as new anti-ageing targets, but the actual clinical significance of the DEJ and its role in aging requires much further research.…”