Role of neurotrophins on dermal fibroblast survival and differentiation

Neurotrophins (NTs) belong to a family of growth factors that play a critical role in the control of skin homeostasis. NTs act through the low-affinity receptor p75NTR and the high-affinity receptors TrkA, TrkB and TrkC. Here we show that dermal fibroblasts (DF) and myofibroblasts (DM) synthesize and secrete all NTs and express NT receptors. NTs induce differentiation of DF into DM, as shown by the expression of \u3b1-SMA protein. The Trk inhibitor K252a, TrkA/Fc, TrkB/Fc or TrkC/Fc chimera prevents DF and DM proliferation. In addition, p75NTR siRNA inhibits DF proliferation, indicating that both NT receptors mediate DF proliferation induced by endogenous NTs. Autocrine NTs also induce DF migration through p75NTR and Trk, as either silencing of p75NTR or Trk/Fc chimeras prevent this effect, in absence of exogenous NTs. Finally, NGF or BDNF statistically increase the tensile strength in a dose dependent manner, as measured in a collagen gel through the GlaSbox device. Taken together, these results indicate that NTs exert a critical role on fibroblast and could be involved in tissue remodelling and wound healin

E-Cadherin mediates UVR- and calcium-induced melanin transfer in human skin cells

yesSkin pigmentation is directed by epidermal-melanin units, characterized by long-lived and dendritic epidermal melanocytes (MC) that interact with viable keratinocytes (KC) to contribute melanin to the epidermis. Previously we reported that MC:KC contact is required for melanosome transfer, that this can be enhanced by filopodial and by UVR/UVA irradiation, which can up-regulate melanosome transfer via Myosin X-mediated control of MC filopodia. Both MC and KC express Ca2+-dependent E-cadherins. These homophilic adhesion contacts induce transient increases in intra-KC Ca2+, while ultraviolet radiation (UVR) raises intra-MC Ca2+ via calcium selective ORAI1 ion channels; both are associated with regulating melanogenesis. However, how Ca2+ triggers melanin transfer remains unclear, and here we evaluated the role of E-Cadherin in UVR-mediated melanin transfer in human skin cells. MC and KC in human epidermis variably express filopodia-associated E-Cadherin, Cdc42, VASP and β-catenin, all of which were upregulated by UVR/UVA in human MC in vitro. Knockdown of E-cadherin revealed that this cadherin is essential for UVR-induced MC filopodia formation and melanin transfer. Moreover, Ca2+ induced a dose-dependent increase in filopodia formation and melanin transfer, as well as increased β-catenin, Cdc42, Myosin X, and E-Cadherin expression in these skin cells. Together these data suggest that filopodial proteins and E-Cadherin, which are upregulated by intracellular (UVR-stimulated) and extracellular Ca2+ availability, are required for filopodia formation and melanin transfer. This may open new avenues to explore how Ca2+ signalling influences human pigmentation

CTACK a new pro-angiogenic factor for dermal endothelial cells

International audienc

CTACK a new pro-angiogenic factor for dermal endothelial cells

International audienc

Notch-1 and Notch-2 modulate keratinocyte stem cell viability and differentiation during skin ageing and UVB exposure

Notch are a family of surface receptors implicated in maintaining epidermal homeostasis. In the epidermis, CK15 and CK10 expression does not change with age, while there is a reduction in Ki67-positive cells and an increased involucrin expression. In culture, keratinocytes display reduced proliferation and a lower colony forming efficiency, as a function of age. Transit amplifying cells appear more affected than stem keratinocytes by ageing. In epidermal sections, Notch-1 expression shows a reduction with age, while Notch-2 is located in the upper layers in Y (under 20-years), in all layers in A (between 20 and 60-years), and predominantly in the basal layer in O (over 60-years). In cultures, Notch-1 activation decreases with age, while Notch-2 seems to be more activated in Y cells than in A and O cells. Notch-1 and Notch-2 are mainly expressed in the cytoplasm of TA cells, Notch-1 being present also in the nucleus. Notch protein inhibition reduces keratinocyte stem cell viability, possibly through survivin downregulation. Inhibiting Notch-1 also induces G1 arrest in keratinocytes at all ages. Notch proteins are activated by calcium, while Notch-1 activation decreases in more differentiated keratinocytes. On the other hand, Notch-2 is activated at cell confluence, in all age groups. Furthermore, Notch-1 is up-regulated upon UVB irradiation (75 mJ/cm2) in Y keratinocytes and is re-activated in O keratinocytes after UVB (5 mJ/cm2). Taken together, these data confirm the role of Notch proteins within epidermal niche and their possible involvement in the mechanisms of photoaging