10.28.22
Shiseido Company says it has discovered that pericyte, which adhere to the outer side of dermal capillaries, may promote epidermal regeneration by moving from the capillary loop to the epidermis and transforming into epidermal stem-like cells. The beauty giant also found that aging causes variance in the direction of capillary loop running toward the epidermis, resulting in the expansion of distance between the capillaries and the epidermis.
After verifying this mechanism, Shiseido said it revealed that Netrin-1 , which is released from the epidermis, increases abnormally with aging and repels the Netrin-1 receptor (UNC5B) expressed at the top of the capillary loop, thereby distancing the capillaries from the epidermis. This phenomenon would inhibit pericyte migration from capillaries in aging skin and reduce the supply of epidermal stem cells. These findings suggest that the supply of epidermal stem cells derived from pericytes may be inhibited in aging skin.
Furthermore, Shiseido says Citrus junos fruit extract suppresses the expression of Netrin-1.
Part of these study results will be presented at the upcoming 47th Annual Meeting of the Japanese Society for Investigative Dermatology and the 30th Annual Meeting of the Japanese Vascular Biology and Medicine Organization, both of which will be held in December.
Going forward, Shiseido said it will continue to create new approaches to beauty by actively elucidating the relationship between beautiful skin and blood vessels, which play an important role in vital functions.
Using its original technology that makes tissues (such as skin) transparent and visualizes their specific structures in three dimensions, Shiseido observed the positional relationship between the capillary network and epidermal stem cells. As a result, it was found that epidermal stem cells exist around the uppermost part of the capillary loop structure, which is distinctively present just below the epidermis, as if they were covering caps. Then, the copany further conducted detailed observation of a single capillary loop by staining the blood vessel, epidermal stem cell, and basement membrane, and discovered that there are cells that cross-link between epidermal stem cells and pericytes adhering to capillaries. This suggests that pericytes attached to capillary loop in the dermis may be detached and supplied to the epidermis as epidermal stem cells. To verify the function of pericytes in this phenomenon, Shiseido isolated pericytes from the skin by using FACS (Fluorescence-Activated Cell Sorting) technology and cell surface proteins that specifically express on pericytes, as an indicator, and cultured them under the conditions in which epidermal cells are cultured. Consequently, the company found that gene expression of p63 and keratin 5, which are characteristics of epidermal cells, increased in pericytes, and that the morphology of pericytes change to epidermis-like cells (Figure 3). Based on these results, we found for the first time in the world that pericytes supplied from the dermal capillary loop may act as epidermal stem cells, contributing to the maintenance of epidermal cells.
Next, Shiseido observed age-induced changes in capillary loop structure. Three-dimensional analysis via skin transparency technology revealed that in young skin, capillary loops are aligned orderly toward the epidermis, whereas in aged skin, the direction of the loops varies, and the distance between the epidermis and capillaries becomes further apart. To elucidate the mechanism of this phenomenon at the molecular level, we measured the expression level of Netrin-1, which is known to inhibit cell migration, as a factor that may affect capillaries, and found that the Netrin-1 expression increased with aging in epidermis. Then, Shiseido analyzed the expression of UNC5B ( known as Netrin-1 receptor and has a repulsive effect on each other) and found that UNC5B appears at the top of the capillary loop. This suggests that in normal skin, Netrin-1 released from the epidermis acts on and repels UNC5B expressed at the top of the capillary loop, preventing the capillaries from invading the epidermis and maintaining the adequate distance. However, the aged skin shows an abnormal level of Netrin-1 production, causing the capillaries to be farther apart from the epidermis than necessary and reduces its ability to pass pericytes from the capillaries to the epidermis, which results in a decrease in the number of epidermal stem cells. Furthermore, Shiseido searched for ingredients that inhibit Netrin-1 expression and found that very effect in citrus junos fruit extract. It is expected that this extract will regulate the delivery of epidermal stem cells from capillaries by appropriately suppressing the excessive expression of Netrin-1 and maintaining the distance between capillaries and epidermis
To date, the skin capillaries have attracted attention for their ability to supply nutrients and oxygen, and much research have been conducted focusing on their role in the dermis. In this study, Shiseido revealed that capillaries also play an important role in the regeneration of epidermis, even without being structurally attached to each other.
After verifying this mechanism, Shiseido said it revealed that Netrin-1 , which is released from the epidermis, increases abnormally with aging and repels the Netrin-1 receptor (UNC5B) expressed at the top of the capillary loop, thereby distancing the capillaries from the epidermis. This phenomenon would inhibit pericyte migration from capillaries in aging skin and reduce the supply of epidermal stem cells. These findings suggest that the supply of epidermal stem cells derived from pericytes may be inhibited in aging skin.
Furthermore, Shiseido says Citrus junos fruit extract suppresses the expression of Netrin-1.
Part of these study results will be presented at the upcoming 47th Annual Meeting of the Japanese Society for Investigative Dermatology and the 30th Annual Meeting of the Japanese Vascular Biology and Medicine Organization, both of which will be held in December.
Going forward, Shiseido said it will continue to create new approaches to beauty by actively elucidating the relationship between beautiful skin and blood vessels, which play an important role in vital functions.
Research Background
Shiseido says it has previously revealed that healthy capillaries may contribute to the suppression of wrinkles and sagging and to the maintenance of skin elasticity through more than 20 years investigating the molecular mechanisms by which skin capillaries maintain dermal homeostasis. Since capillaries are present in the dermis, capillaries were thought to only be loosely associated with the epidermis, which is responsible for the beauty of the skin surface. However, through detailed observation of the positional relationship between capillaries and epidermal cells, the company found that the loop structure of dermal capillaries, which run toward the epidermis, exists much closer to the epidermis than expected, indicating the possibility that capillaries indirectly control epidermal homeostasis. Given that blood vessels are known to form a niche for stem cells in organs throughout the body and promote tissue regeneration, we hypothesized that dermal capillaries have a function that maintains epidermal stem cells and verified the hypothesis using our own advanced visualization technology and molecular biological approach.Using its original technology that makes tissues (such as skin) transparent and visualizes their specific structures in three dimensions, Shiseido observed the positional relationship between the capillary network and epidermal stem cells. As a result, it was found that epidermal stem cells exist around the uppermost part of the capillary loop structure, which is distinctively present just below the epidermis, as if they were covering caps. Then, the copany further conducted detailed observation of a single capillary loop by staining the blood vessel, epidermal stem cell, and basement membrane, and discovered that there are cells that cross-link between epidermal stem cells and pericytes adhering to capillaries. This suggests that pericytes attached to capillary loop in the dermis may be detached and supplied to the epidermis as epidermal stem cells. To verify the function of pericytes in this phenomenon, Shiseido isolated pericytes from the skin by using FACS (Fluorescence-Activated Cell Sorting) technology and cell surface proteins that specifically express on pericytes, as an indicator, and cultured them under the conditions in which epidermal cells are cultured. Consequently, the company found that gene expression of p63 and keratin 5, which are characteristics of epidermal cells, increased in pericytes, and that the morphology of pericytes change to epidermis-like cells (Figure 3). Based on these results, we found for the first time in the world that pericytes supplied from the dermal capillary loop may act as epidermal stem cells, contributing to the maintenance of epidermal cells.
Effect of Citrus Junos Fruit Extract
Next, Shiseido observed age-induced changes in capillary loop structure. Three-dimensional analysis via skin transparency technology revealed that in young skin, capillary loops are aligned orderly toward the epidermis, whereas in aged skin, the direction of the loops varies, and the distance between the epidermis and capillaries becomes further apart. To elucidate the mechanism of this phenomenon at the molecular level, we measured the expression level of Netrin-1, which is known to inhibit cell migration, as a factor that may affect capillaries, and found that the Netrin-1 expression increased with aging in epidermis. Then, Shiseido analyzed the expression of UNC5B ( known as Netrin-1 receptor and has a repulsive effect on each other) and found that UNC5B appears at the top of the capillary loop. This suggests that in normal skin, Netrin-1 released from the epidermis acts on and repels UNC5B expressed at the top of the capillary loop, preventing the capillaries from invading the epidermis and maintaining the adequate distance. However, the aged skin shows an abnormal level of Netrin-1 production, causing the capillaries to be farther apart from the epidermis than necessary and reduces its ability to pass pericytes from the capillaries to the epidermis, which results in a decrease in the number of epidermal stem cells. Furthermore, Shiseido searched for ingredients that inhibit Netrin-1 expression and found that very effect in citrus junos fruit extract. It is expected that this extract will regulate the delivery of epidermal stem cells from capillaries by appropriately suppressing the excessive expression of Netrin-1 and maintaining the distance between capillaries and epidermisTo date, the skin capillaries have attracted attention for their ability to supply nutrients and oxygen, and much research have been conducted focusing on their role in the dermis. In this study, Shiseido revealed that capillaries also play an important role in the regeneration of epidermis, even without being structurally attached to each other.