Keratinocyte Stem Cell Niche: The Role of Neurotrophins and Their Receptors (Pages: 0-0)


Carlo Pincelli *,

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Human epidermis is maintained and renewed by keratinocyte stem cells (KSC). KSC are surrounded by a microenvironment named “niche”, characterized both by the presence of growth factors and by the interactions between cells and the extra-cellular matrix (ECM). Neurotrophins (NT) is a family of growth factors, which control the development, maintenance and apoptotic death of neurons and also fulfill multiple regulatory functions outside the nervous system. Biological effects induced by neurotrophins strongly depend on the patterns of neurotrophin receptor/co-receptors expression on target cells, as well as on the set of intracellular adaptor molecules that link neurotrophin signaling to distinct biochemical pathways. NT exert their functions through two transmembrane receptors, the low-affinity receptor p75 (p75NTR) which binds all NT with equal affinity and the high-affinity receptors trks. TrkA serves as a high-affinity receptor for NGF, TrkB is a high-affinity receptor for BDNF and NT-4, and TrkC is a high-affinity receptor for NT-3. All four NTs interact with the p75NTR receptor. NT form a complex network at the skin level involving most cell types and resulting in a number of autocrine and paracrine activities. Human basal keratinocytes synthesize and secrete biologically active NGF, NT-3, BDNF and NT-4. Furthermore, human keratinocytes express p75NTR, trkA and trkC. Autocrine NGF stimulates keratinocyte proliferation through its high affinity receptor TrkA, while K252, a specific inhibitor of trk phosphorylation, blocks this effect. In addition, K252 and anti-NGF antibodies induce apoptosis in human keratinocytes, indicating that autocrine NGF protects these cells from programmed cell death through its high affinity receptor. NGF is higly expressed in KSC, while it is nearly absent in transit ampligying cells (TA) and postmitotic (PM) cells. TrkA is strongly expressed in KSC and TA cells and disappears in PM cells. Blocking TrkA inhibits KSC proliferation , but does not exert any effect on TA cell proliferation. On the other hand, blocking TrkC, inhibits bot KSC and TA cell proliferation. NGF also induces the up-regulation of Bcl-2 in KSC, as compared to TA cells. p75NTR can signal on its own and mediates cell death. p75NTR is not evenly distributed in the basal keratinocyte layer, but it rather localizes in a subpopulation of basal keratinocytes. p75NTR mRNA is significantly more expressed in TA cells than in KSC. p75NTR protein is absent in KSC, while it is highly expressed in TA cells. p75NTR mediates apoptosis in human keratinocytes, while its role in KSC escaping from the niche is hypothesized. Taken together, these results indicate that NT and their receptors play a critical role within the KSC niche in human epidermis.