Abstract
CD271 is the low-affinity neurotrophin (p75NTR) receptor that belongs to the tumor necrosis factor receptor superfamily. Because in human epidermis, CD271 is predominantly expressed in transit-amplifying (TA) cells, we evaluated the role of this receptor in keratinocyte differentiation and in the transition from keratinocyte stem cells (KSCs) to progeny. Calcium induced an upregulation of CD271 in subconfluent keratinocytes, which was prevented by CD271 small interfering RNA. Furthermore, CD271 overexpression provoked the switch of KSCs to TA cells, whereas silencing CD271 induced TA cells to revert to a KSC phenotype, as shown by the expression of β1-integrin and by the increased clonogenic ability. CD271(+) keratinocytes sorted from freshly isolated TA cells expressed more survivin and keratin 15 (K15) compared with CD271(-) cells and displayed a higher proliferative capacity. Early differentiation markers and K15 were more expressed in the skin equivalent generated from CD271(+) TA than from those derived from CD271(-) TA cells. By contrast, late differentiation markers were more expressed in skin equivalents from CD271(-) than in reconstructs from CD271(+) TA cells. Finally, skin equivalents originated from CD271(-) TA cells displayed a psoriatic phenotype. These results indicate that CD271 is critical for keratinocyte differentiation and regulates the transition from KSCs to TA cells.
Highlights
A fine balance of proliferation, differentiation, and apoptosis is required to maintain epidermal homeostasis (Livshits et al, 2012)
Confluent keratinocytes, cultured under low calcium conditions, appeared to be less differentiated, as confirmed by the low levels of K10 and involucrin. Markers of proliferation, such as cytokeratin 15 (K15) and survivin were downregulated both in subconfluent keratinocytes with calcium and in confluent keratinocytes
When CD271 was silenced by specific CD271 small interfering RNA, calcium treatment only partially induced keratinocyte differentiation, as shown by the reduced levels of involucrin, K10, and epidermal fatty acid–binding protein (Figure 1f and Supplementary Figure S2C online)
Summary
A fine balance of proliferation, differentiation, and apoptosis is required to maintain epidermal homeostasis (Livshits et al, 2012). Continuous epidermal regeneration is accomplished by adult stem cells that are slow-cycling, possess the capacity of self-renew, and remain undifferentiated (Pincelli and Marconi, 2010). Keratinocyte stem cells (KSCs) reside in the basal layer within a microenvironment called niche (Fuchs and Horsley, 2011) and generate transit-amplifying (TA) cells that undergo a limited number of cell divisions before committing to terminal differentiation (Doupeand Jones, 2012). Differentiation begins when cells withdraw from the cell cycle, exit the niche, and detach from the basement membrane and as a function of b1-integrin levels (Watt, 2002; Mulder et al, 2012). The mechanisms triggering the transition from KSCs to TA cells are not fully clarified
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