Elimination of cells unsuitable for young and aging skin

Charles Darwin referred to¹ to natural selection as "a general law leading to the promotion of all organic beings, namely to multiply, to vary, to let live the strongest and the weakest to die". We now know that the concept of Darwin (and Alfred Russel Wallace) also applies to certain mechanisms that govern organ development, tissue maintenance, and aging. Just as different species compete for limited resources and space, the cells of a multicellular organism compete for a niche, while the least fit cells are eliminated to keep the tissues and organs "young". Write in Nature, Liu et al.² give an overview of how the tissue's youth is maintained and mechanisms that regulate the aging process of epithelial organs such as the skin.

Natural selection has favored tissue care programs that delay the dieback of an animal's body while it is likely to reproduce successfully.³. After this reproductive period, tissue maintenance programs gradually lose their ability to limit the accumulation of damage to stem cells and their niches. This ultimately leads to a loss of tissue function and physical fitness, characteristics that characterize aging. Human aging is prevalent in modern industrialized environments in which external threats to survival are negligible. Liu et al. used the skin of the mouse tail as a model for the aging of human skin.

Mammalian skin consists of two compartments: a layered multilayered upper epithelium called epidermis and a thicker and thicker layer of connective tissue called the dermis.⁴. A thin layer of extracellular proteins, called the basement membrane, connects these two compartments. The cells of the epidermis are continually renewed with cells differentiating from stem cells and other progenitor cells located in the deepest layer of the epidermis, the basal layer. These cells of the basal layer are anchored to the basement membrane via highly specialized multiprotein structures called hemidesmosomes.⁴.

The protein called collagen type XVII is one of the main components of hemidesmosomes. Reduced levels of this type of collagen (encoded by the gene COL17A1and therefore known as COL17A1 protein) characterize cutaneous aging⁵. Liu et al. show that the number of hemidesmosomes in the skin of the mouse tail decreases with age and that this reduction is correlated with low levels of COL17A1. The loss of COL17A1 destabilizes the other components of the hemidesmosome and ultimately prevents the formation of these structures. Liu et al. Then show that COL17A1 is the least stable component of hemidesmosomes in mice and also in human epidermal cells in culture. COL17A1 degrades rapidly in response to several types of stress, including DNA damage resulting from exposure to ultraviolet light.

Liu et al. also traced the fate of the epidermal cells of the basal layer in mice. As these animals age, epidermal stem cells expressing high levels of COL17A1 preferentially propagate at the expense of stem cells with low levels of COL17A1, which makes epidermal cells more clonal (i.e. they come from fewer different stem cells). This finding is consistent with the observation that blood cells in older adults are more clonal than those in younger people⁶.

The authors then used a mouse model in which the expression of COL17A1 could be turned off in a limited number of epidermal cells of the basal layer. The loss of COL17A1 in some epidermal stem cells triggered cell competition to obtain space in the basal layer. The "unfit" cells with low levels of COL17A1 were not dead, but were removed from the basal layer and replaced with "fit" cells that expressed high levels of COL17A1 (Fig 1). Experiences using a in vitro human skin model corroborated these findings. Reduction of COL17A1 expression in basal epidermal cells resulted in detachment of these basement membrane cells when a sufficient number of cells expressing high levels of COL17A1 were present to compete with low expressing cells. COL17A1 level.

The authors found that high levels of COL17A1 in mice favored the maintenance of stem cells by stimulating basal cell divisions in a plane parallel to that of the basement membrane. This mechanism explains the increasingly clonal characteristics of cells expressing high levels of COL17A1 during aging. The loss of COL17A1 stimulates cell division of the basal layer in a plane perpendicular to that of the basement membrane. These divisions are necessary to produce differentiated epidermal cells of the non-basal layers of the skin.

However, too many of these perpendicular divisions eventually cause stem cell deficiency and other skin defects associated with aging, such as thinning of the epidermis and depigmentation due to the loss of pigmentary stem cells from the skin. When Liu and his colleagues restored the expression of COL17A1 by genetic modification, the stem cells of the epidermis thus regained the ability to compete within the basal layer and partially attenuated skin aging.

Collectively, these results suggest that COL17A1 is a sensor of DNA damage and aging epidermal stem cells. In young skin, spontaneous damage to DNA in a limited number of basal cell cells promotes the degradation of COL17A1, which alters the formation of hemidesmosomes, reduces cell adhesion to the basement membrane and triggers division. perpendicular cell. Undamaged basal cell cells with high and healthy levels of COL17A1 maintain parallel cell divisions and expand horizontally – effectively eliminating less-shaped basal layer cells and promoting youthful skin. A lifetime of epidermal stem cell injury ultimately reduces the overall level of COL17A1 to a critical threshold at which normal hemidesmosome formation is impaired. In this situation, there are fewer cells in good shape that compete with less fit cells, resulting in the depletion of skin stem cells, thinning and fragility of the epidermis and depigmentation of the skin (Fig. 1).

Maintaining stem cells in good condition during the years in which an individual is likely to reproduce probably also prevents tumor development, as these healthy cells compete with (and eliminate) damaged stem cells and prone cells to tumors⁷. In particular, it has been shown that cell competition promotes the expulsion of epithelium from cells with mutations causing tumors or other abnormal characteristics.^8,9.

Although cell competition has been widely studied in fruit flies^tenLiu and his colleagues demonstrate that healthy mammalian cells can also effectively repopulate adult tissue, replacing unfit or damaged cells. Similar competitive interactions can sometimes be observed between cells in good condition and those that are not in people with an inherited skin disease called junctional epidermolysis bullosa (JEB), caused by gene mutations encoding COL17A1. and other components of the dermal-epidermal junction.¹¹.

People with JEB have severe blisters on the skin due to structural abnormalities in their hemidesmosomes and their dermal-epidermal junction.¹¹. Some affected people have reduced pigmentation on healed ampoules sites¹¹ and have an abnormally low number of skin stem cells¹². This last observation is in correlation with the conclusions of Liu and his collaborators that a good adhesion of the epidermis to the basement membrane facilitates the maintenance of the stem cells of the skin. Notably, many, if not all, people with JEB due to COL17A1 mutations have normal and un-swollen skin plaques resulting from a competitive expansion of cells in which the COL17A1 defect has been spontaneously corrected.^13,14 – a form of natural gene therapy. These patches, called "reverting skin patches," have normal pigmentation¹³, which is consistent with Liu's conclusion et al. COL17A1 also plays a key role in the maintenance of pigmentary stem cells in the skin.

In addition to elucidating the mechanisms of skin aging, Liu et al. identify two chemicals that can induce the expression of COL17A1 in epidermal cells and improve the ability of skin stem cells to regenerate. Both chemicals improve wound healing in the skin of the mouse tail, providing a proof of principle of the therapeutic potential of this new class of drugs. Future studies are needed to determine the mechanisms of cellular competition in other tissues and to identify compounds able to reverse aging in other organs.