Organ-Level Quorum Sensing Directs Regeneration in Hair Stem Cell Populations

Abstract

SUMMARY Coordinated organ behavior is crucial for an effective response to environmental stimuli. By studying regeneration of hair follicles in response to patterned hair removal, we demonstrate that organ-level quorum sensing allows coordinated responses to skin injury. Removing hair at different densities leads to a regeneration of up to 5 times more neighboring, unplucked resting hairs, indicating activation of a collective decision-making process. Through data modeling, the range of the quorum signal was estimated to be on the order of 1 mm, greater than expected for a diffusible molecular cue. Molecular and genetic analysis uncovered a two-step mechanism, where release of CCL2 from injured hairs leads to recruitment of TNF-α secreting macrophages, which accumulate and signal to both plucked and unplucked follicles. By coupling immune response with regeneration, this mechanism allows skin to respond predictively to distress, disregarding mild injury, while meeting stronger injury with full-scale cooperative activation of stem cells.

Effects of Imiquimod on Hair Follicle Stem Cells and Hair Cycle Progression

“…12 injury (Chen et al, 2015). Both these cytokines were barely detectable in the skin of untreated mice, and upregulated after IMQ treatment during late Telogen, but not during early Telogen ( Fig.…”

“…HFSC activity is highly controlled, not only by stem cell-derived factors, which can be either inhibitory or activating, but also by immune cell-or other dermal cell-derived factors, like Bmp2, Bmp4, Wnt10, Dkk1, Follistatin, Noggin, Sfrp4, and TNFα (Botchkarev, 2001;Castellana et al, 2014;Chen et al, 2014;Chen et al, 2015;Plikus et al, 2008). Since IMQ leads to infiltration of different immune cell populations into the skin it is very likely that they affect HFSC and hair cycle progression.…”

The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration

“…Additionally, Nestin is a marker of stem cells in many tissues, including the brain and skin, yet aberrant activation of Nestin in liver tumors drives cell plasticity and malignancy (Li et al 2003;Toma et al 2005;Tschaharganeh et al 2014;Neradil and Veselska 2015). Furthermore, while NFKB is a potent mediator of age-and tumor-associated inflammation and dedifferentiation, it also contributes to HFSC regeneration upon skin wounding (Chen et al 2015) and is a key driver of hair follicle initiation and development (Schmidt-Ullrich et al 2001;Zhang et al 2009), further supporting how NFKB-mediated processes regulating normal tissue development and regeneration can contribute to tumor formation and cancer stem cell fate when misregulated (Myant et al 2013;Schwitalla et al 2013). It is also interesting here that cells that bypass senescence arrest through knockdown of p16 still retain expression of the stem cell signature and now exhibit increased clonal growth capacity, suggesting that escape from senescence may lead to more aggressive cancer stem cell properties mediated by NFKB and a retained SASP.…”

FOXC1 maintains the hair follicle stem cell niche and governs stem cell quiescence to preserve long-term tissue-regenerating potential

“…Termed the "niche," it not only provides a residence for SCs, but also interacts with SCs to regulate their behavior and properties (3,4). Niche signals can take the form of short-range cues from the immediate neighbors of the SCs, or longer-range signals from the macroenvironment of the organ (5)(6)(7)(8). Together, these signals ensure that SCs are used efficiently to meet tissue-specific physiological needs.…”