Transit-Amplifying Cells Orchestrate Stem Cell Activity and Tissue Regeneration

Abstract

SUMMARY Transit-amplifying cells (TACs) are an early intermediate in tissue regeneration. Here, using hair follicles (HFs) as paradigm, we show that emerging TACs constitute a signaling center that orchestrates tissue growth. While primed stem cells (SCs) generate TACs, quiescent-SCs only proliferate after TACs form and begin expressing Sonic Hedgehog (SHH). TAC generation is independent of autocrine SHH, but their pool wanes if they can’t produce it. We trace this paradox to two direct actions of SHH: promoting quiescent-SC proliferation and regulating dermal factors that stoke TAC expansion. Ingrained within quiescent-SC’s special sensitivity to SHH signaling is their high expression of GAS1. Without sufficient input from quiescent-SCs, replenishment of primed-SCs for the next hair cycle is compromised, delaying regeneration and eventually leading to regeneration failure. Our findings unveil TACs as transient but indispensable integrator of SC niche components and reveal an intriguing interdependency of primed and quiescent SC populations on tissue regeneration.

Roles for Hedgehog signaling in adult organ homeostasis and repair

“…Conversely, exogenously administered SHH triggers anagen onset in resting hair follicles and stimulates hair growth (Sato et al, 1999). Consistent with these early reports, recent evidence of Shh expression by the committed progeny of stem cells within the anagen follicle has revealed a feedback mechanism whereby SHH+ progenitor cells signal to their parental quiescent stem cells in the bulge region to trigger stem cell activation and proliferation (Hsu et al, 2014). Whereas removal of Shh expression in the hair germ caused marked proliferative defects throughout the hair follicle, genetic abrogation of Smo or Gli2 alone in the stem cells reduced their proliferative abilities but did not affect anagen progression, indicating that SHH is required to maintain the function of hair follicle stem cells but not that of the progenitor cells in which it is expressed.…”

“…Whereas removal of Shh expression in the hair germ caused marked proliferative defects throughout the hair follicle, genetic abrogation of Smo or Gli2 alone in the stem cells reduced their proliferative abilities but did not affect anagen progression, indicating that SHH is required to maintain the function of hair follicle stem cells but not that of the progenitor cells in which it is expressed. The same study revealed a secondary effect of progenitor-secreted SHH, namely to stimulate the expression of factors such as FGF7 (fibroblast growth factor 7) and NOG (noggin) by the dermal papilla, which in turn help to maintain the expansion of the progenitor pool (Hsu et al, 2014). Exactly how this feed-forward mechanism is regulated and ultimately extinguished remains to be determined.…”

Wnt some lose some: transcriptional governance of stem cells by Wnt/β-catenin signaling

“…3A; Pereira et al 2006;Tam et al 2008), and when Wnt signaling is activated or TCF3 is absent, core pluripotency factors are up-regulated (Cole et al 2008;Yi et al 2011). When combined with the recent findings of Chodaparambil et al (2014) and the findings delineated for the hair follicle above (Merrill et al 2001;Nguyen et al 2006Nguyen et al , 2009Greco et al 2009;Hsu et al 2014;Lien et al 2014), these findings suggest that binding of b-catenin to TCF3 alters the TCF3-bound repressive chromatin state, in turn activating target genes (Fig. 3B).…”

“…Reductions in BMP signaling and elevation of canonical Wnt signaling are necessary to stabilize b-catenin, repress TCF3/4, and activate LEF1 to send the stem cells along the hair differentiation lineage ( Fig. 4A; Greco et al 2009;Hsu et al 2014). It remains to be determined whether this switch involves Wnt/b-catenin-mediated targeting of TCF3/4 for proteasomal degradation, as happens in murine ES cells (Shy et al 2013), or phosphorylation-dependent relief of TCF3/4 binding to its chromatin sites, as reported in Xenopus (Hikasa et al 2010;Hikasa and Sokol 2011).…”

“…These primed HG progenitors have a lower threshold for activation when receiving stimulating cues from the niche (Greco et al 2009). However, once these progenitors get activated and form the pool of transit-amplifying progeny, self-renewal of the HFSCs to replenish the niche is accomplished by Shh signaling emanating from the transient amplifying cells (TACs) (Hsu et al 2014). This proliferation is brief: Soon, the TACs (and their Shh signal) and the DP (and their BMP inhibitory signals) move too far away from the stem cell niche, which then returns to quiescence (Hsu et al 2011(Hsu et al , 2014.…”