Glycobiology to the rescue ! (2016)

Epidermal homoeostasis is maintained by a fine balance of keratinocyte proliferation and terminal differentiation. In skin homoeostasis, cells which enter the differentiation programme must be compensated by cell replenishment in the epidermal basal layer. Today, it is admitted that two distinct proliferative cells coexist in the basal layer of epidermis, namely slow-cycling stem cells and committed progenitor cells.1 Keratinocyte stem cells can self-renew (symmetric division) and give rise to one stem cell and one committed progenitor (asymmetric division) and sometimes to two committed progenitors. In this regard, CD271 expression in human epidermis is a landmark of early progeny transition from keratinocyte stem cell to transit-amplifying cells,2 while high β1 integrin and melanoma-associated chondroitin sulphate proteoglycan (MCSP) expression identifies these basal keratinocytes with the highest in vitro self-renewal.3 These MCSP+/β1Hi cells are confined to the top of rete ridges. From a functional point of view, self-renewing keratinocytes will produce in vitro large proliferating clones called holoclones, while transit-amplifying cells will generate intermediate wrinkled clones called meroclones and highly committed cells will generate small differentiated clones called paraclones.4 Of note, the basement membrane and the uppermost dermis are key components of the epidermal stem cells' niche.5 From a histological point of view, skin ageing is mainly characterized by a flattening of the dermal–epidermal junction, an epidermal thinning in some body sites like scalp, a decreased basal cell density, a delamination of the basement membrane and alteration of the superficial dermis.6 Of note, the most striking alterations reported so far deal with extracellular matrix and more precisely, with decreased expression of glycosaminoglycans and related proteoglycans.7 Two major components of the basal membrane are strongly diminished, namely heparan sulphate and perlecan, while in the upper dermis, the expression of both versican and decorin decreases with age. With respect to human epidermal stem cells, CD271+ cells diminish with age,8 as well as high-β1-integrin- and MCSP-expressing cells.3 In parallel, the ability to in vitro give rise to holoclones progressively decline while the number of paraclones increases.4 Of note, in human hair follicles, an age-related progressive decline in holoclone production was also observed.9 Altogether, these results suggest an age-related progressive loss of human epidermal stem cells' functionality. In a recently published issue, Charruyer et al.10 show that in the presence of phycosaccharide AI, a high molecular weight (3500 Da) alginate polysaccharide containing alternate structures of sodium mannuronate and sodium guluronate, keratinocytes isolated from aged individuals (61 to 79 years old) give rise to an increased number of large and highly proliferative colonies compared to untreated cells. Moreover, holoclone formation and asymmetric divisions increases, indicating a stimulation of stem cell self-renewal. Interestingly, this phycosaccharide effect was stronger in ‘old’ than in young keratinocytes, suggesting that phycosaccharide treatment restored some in vitro epidermal stem cell functionality that had been progressively lost during ageing. These results highlight the key role of glycans at controlling skin homeostasis and in this reported study, at maintaining and/or restoring full functionality of human epidermal stem cells in vitro. Of course, it would be of great interest to follow the in vivo effect of this phycosaccharide AI, specifically on CD271, β1 integrin and MCSP expression in the epidermal basal layer of skin from old donors. A possible effect on the quality of dermal–epidermal junction (DEJ) and restoration of perlecan expression should also be investigated, as the DEJ is a key component of the epidermal stem cell niche.5 Indeed the quality of DEJ in old skin can be restored by treatment with a C-xylopyranoside, which stimulates skin expression of glycosaminoglycans and heparan sulphate proteoglycans.11 Taken together, these results demonstrate that manipulating the glycan environment of human epidermal stem cells is a promising approach to restore their full functionality and to maintain epidermal homoeostasis. More generally speaking, glycans which are endowed with a unique and huge molecular diversity, represent the third language of life, besides nucleic acids and proteins,12 and as such, must be taken into consideration more fully as key actors of skin biology and important factors in investigative dermatology. Considering the molecular structure of glycans that can be revealed by the use of fluorescently labelled lectins, it is already clear that each skin compartment can be identified by specific lectins and hence specific glycan signatures (Fig. 1).13 This suggests that skin is endowed with a complex, but so far underestimated, glycobiology. With respect to epithelial stem cell activities, proteoglycans are known to modulate Wnt signalling cascades, to shape Hedgehog gradients and signal transduction and to control Notch1 interaction with its cognate Delta-like 4 receptor (see 14 for a review). The role of glycans would obviously not be restricted to interfollicular skin biology, as a number of papers argue for a key role of glycans in the control of human hair follicle growth and cycling.14 To conclude, results reported by Charruyer et al.10 represent an additional progress in our understanding of as yet insufficiently explored key role of glycan components in skin biology. The author's work also demonstrates the value of in vitro colony-forming efficiency tests to detect glycan active compounds that modulate epidermal stem cell . Of course, any such putative activity will have to be confirmed and validated in the in vivo situation. The authors have declared no conflicting interests.