Stem cell dynamics in mouse hair follicles: A story from cell division counting and single cell lineage tracing

Abstract

Understanding tissue stem cell behavior is a prerequisite for elucidating the mechanisms that govern their self-renewal and differentiation. Previously, we provided single cell lineage tracing and proliferation history data (based on H2B-GFP label dilution over time) in mouse hair follicles. We proposed a population deterministic model with symmetric stem cell fate decisions throughout life. Here we provide data suggesting that in hair follicle stem cells the self-renewing divisions within the niche (bulge) are symmetric with respect to localization of daughter cells near the basement membrane, an important niche component. In contrast, when cells migrate from the niche to the differentiating zone where they become short-lived progenitors, their daughter cells can adopt assymetric orientation relative to the basement membrane. Furthermore, we document the dynamic re-localization of cells within the bulge to accommodate the hair follicle morphological changes through the hair cycle. In addition, we provide a method to compute the change in number of cells generated by division from H2B-GFP pulse-chase data, and to estimate the minimum cell loss encountered when the fold change can be experimentally determined. We computed a minimum of 42% of bulge cell loss during one hair cycle, a massive rate of loss previously unrecognized. Finally, we showed that a multipotent population of cells found at the junction zone between hair follicle and epidermis, known to express Lrig1, cycle more rapidly than some other hair follicle compartments.

The in vivo function of mammalian cell and tissue polarity regulators – how to shape and maintain the epidermal barrier

“…However, it has been debated whether these cells truly represent long-lived stem cells. In mice, the hair follicle bulge harbours the most pluripotent stem cells and lineage tracing experiments in this system suggest that symmetric divisions replenish these cells (Petersson et al, 2011;Zhang et al, 2010). This is consistent with findings that hair follicle stem cells do not oblige with the 'immortal strand' hypothesis (Sotiropoulou et al, 2008;Waghmare et al, 2008).…”

“…This proposes that stem cells asymmetrically segregate their chromosomes to retain the same strand of DNA over several divisions in order to avoid accumulating DNA mutations. Progenitors located just below the bulge in the hair germ (Greco et al, 2009) can divide asymmetrically (Zhang et al, 2010) and some recent evidence suggest that these cells replenish bulge stem cells while at the same time providing enough cells to drive anagen hair follicle growth (Hsu et al, 2011) (Fig. 4).…”

Tcf3 expression marks both stem and progenitor cells in multiple epithelia

“…; P=0.42, Mann-Whitney U-test) in the number of labeled follicles from 3 days to 6 months post induction (supplementary material Fig. S2F), consistent with a model in which most or all HF bulge cells possess stem cell potential but are occasionally lost from the stem cell niche, as previously described by others (Hsu et al, 2011;Zhang et al, 2010).…”

Tracing epithelial stem cells during development, homeostasis, and repair

“…1, B and C). Clonal analysis of bulge SCs indicated that some bulge SCs can differentiate into all HF lineages, whereas others are com mitted to either the outer or the inner cell layers (Legué et al, 2010;Zhang et al, 2010). These results suggest that the hetero geneity in the differentiation potential of bulge SCs is either related to an intrinsic heterogeneity of bulge cells containing multipotent and unipotent SCs or through a regulation of the lineage differentiation potential of multipotent SCs.…”