Paracrine crosstalk between endothelial cells and melanocytes through clusterin to inhibit pigmentation

Abstract

Cutaneous vasculature systems play a role in regulating skin pigmentation. We analysed RNA sequencing data to identify novel antimelanogenic factors secreted from endothelial cells and found that one of the secreted factors, clusterin, is highly expressed by HDMECs.To investigate the paracrine effect of clusterin from HDMECs on the regulation of melanogenesis, HDMECs were infected with clusterin or sh-clusterin lentivirus and the HDMEC-derived conditioned media were used to treat normal human melanocytes. It was found that HDMEC-derived clusterin inhibits melanogenesis through MITF/ tyrosinase downregulation. The findings here suggest that HDMECs secrete copious amounts of clusterin and that the clusterin is a factor contributing to the inhibitory effect of endothelial cells on melanogenesis via paracrine crosstalk between endothelial cells and melanocytes. | BACKGROUNDMelanocyte activity is regulated under the influence of paracrine factors secreted by neighbouring cutaneous cells, such as keratinocytes or fibroblasts [1][2][3]. Very recently, it was suggested that cutaneous vasculature plays a role in regulating skin pigmentation and perhaps its dysfunction in pigmentary diseases [4,5]. Conversely, a regulatory function of melanocytes on vascularization was also discovered, suggesting paracrine crosstalk between endothelial cells and melanocytes [6]. Endothelial cells produce prostaglandins, nitric oxide or endothelin-1 for pigmentation regulation [7]. We previously showed that endothelial cells reduce pigmentation and that TGFβ1 could be considered as a secreted factor through which HDMECs inhibit mel- | QUESTION ADDRESSEDIn this study, we analysed RNA sequencing data to identify novel antimelanogenic factors secreted from endothelial cells. There is a high level of the expression of the clusterin gene in HDMECs. Because clusterin is known to be an extremely sensitive biosensor of oxidative stress and inflammation in human tissues [9,10], and given that clusterin signalling reportedly has regulatory effects on melanoma growth [11], this result was of interest. We therefore investigated the expression of clusterin in HDMECs in the skin and the in vitro effect of HDMEC-derived clusterin on pigmentation. | EXPERIMENTAL DESIGNThe endogenous expression of clusterin in endothelial cells was in- | RESULTSHDMECs highly expressed clusterin ( Figure 1A | CONCLUSIONIn this study, we demonstrated that HDMECs secrete copious amounts of clusterin and that clusterin is a major factor contributing the inhibitory effect of endothelial cells on melanogenesis. Melanocytes reduced the expression of tyrosinase through the down-expression of MITF responding to the HDMEC-derived clusterin. The in vivo biological role of clusterin is presently unclear; however, it is likely that in a physiologic situation, cutaneous vascular endothelial cells secrete clusterin as well as TGFβ1 and play a role in maintaining low levels of pigment production [8]. Clusterin is also secreted from skin fibroblasts [12,13], and very recently, we...

Quantitative proteomics analysis of young and elderly skin with DIA mass spectrometry reveals new skin aging-related proteins

“…Aged skin samples showed upregulated expression of clusterin (CLU), a chaperone that inhibits both accumulation of elastin in photoaged skin [ 58 ] and melanogenesis through MITF/tyrosinase downregulation [ 59 ]. These actions may be related to characteristic phenotypes (e.g.…”

Alterations of the pigmentation system in the aging process

“…Compared with the perilesional normal skin, the hyperpigmented skin has been found to exhibit an upregulated expression of vascular endothelial growth factor (VEGF), a major angiogenic factor in UV‐exposed skin (Kim et al., 2007). Endothelial cells produce both melanogenic factors, such as nitric oxide and ET‐1 (Regazzetti et al., 2015; Suschek et al., 2004) and anti‐melanogenic factors, such as TGFβ1 and clusterin (Jo et al., 2009; Kim, Lee, et al., 2018; Kim, Shibata, et al., 2018; Park et al., 2016). These secretory factors derived from endothelial cells probably play regulatory roles in skin pigmentation.…”

Ultraviolet-irradiated endothelial cells secrete stem cell factor and induce epidermal pigmentation

“…Several recent studies have highlighted the paracrine crosstalk between endothelial cells and melanocytes 14 – 17 . A recent study reported the regulatory function of melanocytes in vascularization, wherein choroidal melanocytes regulated uveal vascularization through the secretion of fibromodulin 16 .…”

“…On the contrary, a regulatory function of endothelial cells on melanocytes was discovered. Under physiological conditions, endothelial cells increase pigmentation by releasing endothelin-1 or inhibit pigmentation via transferrin growth factor (TGF)-β or clusterin 14 , 15 , 17 . However, how UV irradiation produces changes in endothelial cell secretions in relation to epidermal pigmentation is questionable.…”