The p75 neurotrophin receptor triggers keratinocyte stem-transit amplifying cell transition in normal human epidermis

Abstract

p75 neurotrophin (NT) receptor (p75NTR) can signal independently from the high affinity receptor Trk and mediates apoptosis in human keratinocytes, upon binding with specific ligands. As p75NTR is predominantly expressed in transit amplifying (TA) cells, we aimed to study the role of p75NTR in keratinocyte differentiation. p75NTR was up-regulated during keratinocyte differentiation in cell culture with both serum and calcium treatment. When p75NTR was silenced, calcium treatment failed to induce differentiation in subconfluent keratinocytes. p75NTR positive (p75NTRpos) human keratinocytes, isolated by cell sorting, were less differentiated, as shown by western blotting and confocal analysis, and proliferated less than p75NTR negative (p75NTRneg) cells. In human skin sections, p75NTR was confined to a MIB-1 negative cell population, while some p75NTR positive cells expressed CK15 and survivin, which preferentially identify keratinocyte stem cells (KSC). Freshly isolated p75NTRpos TA cells expressed more survivin and CK15, while displayed less CK10 than p75NTRneg TA. p75NTRpos TA cells produced more colonies, proliferated to a greater extent, and yielded a higher number of cells than p75NTRneg TA, suggesting that p75NTRpos cells are early TA cells. Moreover, p75NTR retroviral infection of KSC induced a more differentiated phenotype, with the same features of TA cells. Finally, p75NTRpos TA cells generated a skin reconstruct where CK10 was more homogeneously expressed than in skin originated from p75NTRneg TA cells. These results suggest that p75NTRpos keratinocytes represent a subpopulation of TA cells, that just started the differentiation process from KSC. p75NTR may act as a “switch on-off” protein in stem-TA transition, initiating keratinocyte differentiation. JSID AbstractsJournal of Dermatological ScienceVol. 69Issue 2Preview Full-Text PDF