Bimodal behaviour of interfollicular epidermal progenitors regulated by hair follicle position and cycling

Abstract

Interfollicular epidermal (IFE) homeostasis is a major physiological process allowing maintenance of the skin barrier function. Despite progress in our understanding of stem cell populations in different hair follicle compartments, cellular mechanisms of IFE maintenance, in particular, whether a hierarchy of progenitors exists within this compartment, have remained controversial. We here used multicolour lineage tracing with Brainbow transgenic labels activated in the epidermis to track individual keratinocyte clones. Two modes of clonal progression could be observed in the adult murine dorsal skin. Clones attached to hair follicles showed rapid increase in size during the growth phase of the hair cycle. On the other hand, clones distant from hair follicles were slow cycling, but could be mobilized by a proliferative stimulus. Reinforced by mathematical modelling, these data support a model where progenitor cycling characteristics are differentially regulated in areas surrounding or away from growing hair follicles. Thus, while IFE progenitors follow a non-hierarchical mode of development, spatiotemporal control by their environment can change their potentialities, with far-reaching implications for epidermal homeostasis, wound repair and cancer development.

Type XVII collagen coordinates proliferation in the interfollicular epidermis

“…The discordance between the paw epidermis and back skin IFE might be explained either by the influence of hair follicle development on the back skin IFE or by the distinct regulation of the IFE at each body site (Rompolas et al, 2016; Roy et al, 2016; Sada et al, 2016). We also investigated cell-intrinsic properties due to COL17 defects using cultured normal human epidermal keratinocytes (NHEKs).…”

Skin and Its Regenerative Powers: An Alliance between Stem Cells and Their Niche

“…When pulse-chase analyses were used to examine radiolabeled nucleotide or H2BGFP fluorescence dilution within the proliferative basal populations of paw, ear, or scale regions of tail skin epidermis, progenitors divided more frequently, with estimates of divisions every 2–5 days (Doupe et al, 2010; Lim et al, 2013; Sada et al, 2016). Interestingly, however, when Roy et al (2016) crossed Krt14-CreER and Rainbow mice to conduct multicolor lineage tracing and track individual back skin epidermal clones, they discovered that the clones nearest to actively cycling HFs were considerably more proliferative than the ones more distant (Roy et al, 2016). Given the variation in HF densities at different body sites, this may explain some of the heterogeneity seen among basal cell populations from different body sites.…”

“…In reviewing the collective studies on epidermal progenitors, it seems clear that most of the differences in interpretation have arisen from whether progenitor fates were assigned according to molecular differentiation markers (Clayton et al, 2007; Mascre et al, 2012), basal residence status (Roy et al, 2016; Sada et al, 2016), or the ability of two daughters to divide at least once prior to exiting the basal layer (Rompolas et al, 2016). Additional confusion has arisen from whether researchers have assigned stemness according to cell-cycling rates (Lim et al, 2013) or according to clonal longevity (Sada et al, 2016).…”

Concise Review: Wnt Signaling Pathways in Skin Development and Epidermal Stem Cells

“…On the other hand, using live imaging techniques, Rompolas and colleagues support the stochastic model and demonstrate that IFE basal cells are born as uncommitted SCs which have equal potential to proliferate or undergo differentiation . In agreement, a recent study using multicolor lineage tracing shows that the IFE can be maintained without a hierarchy of SCs and TACs . The tools used to mark basal cells and examined epidermal regions at different body sites are likely to account for the differences among these studies.…”