Nfatc1 orchestrates aging in hair follicle stem cells

Abstract

Hair production is fueled by stem cells (SCs), which transition between cyclical bouts of rest and activity. Here, we explore why hair growth wanes with age. We show that aged hair follicle SCs (HFSCs) in mice exhibit enhanced resting and abbreviated growth phases and are delayed in response to tissue-regenerating cues. Aged HFSCs are poor at initiating proliferation and show diminished self-renewing capacity upon extensive use. Only modestly restored by parabiosis, these features are rooted in elevated cell-intrinsic sensitivity and local elevation in bone morphogenic protein (BMP) signaling. Transcriptional profiling presents differences consistent with defects in aged HFSC activation. Notably, BMP-/calcium-regulated, nuclear factor of activated T-cell c1 (NFATc1) in HFSCs becomes recalcitrant to its normal down-regulating cues, and NFATc1 ChIP-sequencing analyses reveal a marked enrichment of NFATc1 target genes within the age-related signature. Moreover, aged HFSCs display more youthful levels of hair regeneration when BMP and/or NFATc1 are inhibited. These results provide unique insights into how skin SCs age.BMP signaling | hair cycle | quiescence I n adult tissues, stem cells (SCs) must replace cells lost to acute injury and normal biological activity (homeostasis). Aging can be viewed as a failure to maintain proper tissue homeostasis, resulting in a decline in tissue function and delayed response to tissue damage (1). Age-related extrinsic changes in external, systemic, and/or local tissue environment, coupled with intrinsic changes from repetitive use, are all potential underlying causes for SC malfunction. However, the relative contributions of these factors on SC aging vary among SC populations. Studies on hematopoietic and melanocyte SCs show that age-related intrinsic perturbations can impair SC function (2-4). Mesenchymal SCs, cardiac SCs, and liver progenitor cells also show age-related declines in performance (5-7). The impact of extrinsic perturbations is evident from studies on muscle and neural SCs, where exposure to a youthful systemic environment can restore SC functional capabilities (7-10). Most recently, it was shown that cardiomyocytes rely upon systemic growth and differentiation factor 11 (GDF11), a member of the transforming growth factor β (TGF-β) superfamily, which declines with age (11).The skin has some of the most recognizable age-associated changes. In humans and other mammals, skin shows an agerelated decline in homeostasis, with both dermal and epidermal thinning, reductions in epidermal proliferation and injury repair, loss of dermal elasticity, wrinkling, and notably, hair thinning and eventual loss (12). Periods of rest in hair follicles (HFs) also become longer as animals age, and in humans, hair density declines with age. It has been suggested that the progressive dormancy of HFs during aging is a reflection of a declining capacity of SCs to initiate a new hair cycle, but this has not been formally tested and the underlying mechanisms remain largely unexplored.HFs underg...

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

“…While canonical Wnt signaling affects the behavior of many adult stem cells, signaling can be high or low depending on the stem cells and their niche. In the quiescent HFSC niche, perceived Wnt signaling is low, corresponding to the high levels of TCF3, TCF4, and TLEs as well as BMP and calcium signaling, which leads to high levels of nuclear NFATc1, typically viewed as a noncanonical Wnt effector (DasGupta and Fuchs 1999;Merrill et al 2001;Horsley et al 2008;Keyes et al 2013;Lien et al 2014). 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.…”

Calcineurin/Nfatc1 signaling links skin stem cell quiescence to hormonal signaling during pregnancy and lactation

“…Thus, distinct mechanisms seem to regulate Prlr expression in different keratinocyte populations. While Nfatc1-independent mechanisms control Prlr expression in the IFE, Nfatc1 promotes Prlr expression in HF SCs, which is likely due to a direct mechanism, since Nfatc1 physically associates with the Prlr promoter in bulge cells (Keyes et al 2013). …”

“…Nfatc1 inhibition induces hair growth through precocious bulge cell proliferation (Horsley et al 2008), and it is not clear whether Nfatc1 inhibition accelerates bulge cell migration to induce HF growth, as in the native hair cycle (Zhang et al 2009). Although CN and Nfatc1 have been implicated in epidermal SC function via distinct molecular events (Horsley et al 2008;Wu et al 2010;Keyes et al 2013), the global role of this signaling pathway in regulating skin SC quiescence has not been fully elucidated.…”

Young plasma reverses age‐dependent alterations in hepatic function through the restoration of autophagy

“…found that the muscle and liver from the aged partner of the heterochronic pairs exhibited youthful levels of regeneration (Conboy et al., 2005). A similar “rejuvenating” effect of young blood has been demonstrated in other organs, including the spinal cord (Ruckh et al., 2012), heart (Loffredo et al., 2013), brain (Katsimpardi et al., 2014) (Villeda et al., 2014), β‐cells (Salpeter et al., 2013), and hair follicles (Keyes et al., 2013). Collectively, these observations suggest that exposure to a “young” environment could prevent or reverse age‐dependent decline in the function of critical organ systems.…”