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

Goldstein, Jill M.; Fletcher, Sean A.; Roth, Eve; Wu, Chuansha; Chun, Andrew S.; Horsley, Valerie

doi:10.1101/gad.236554.113

Cited by 43 publications

(34 citation statements)

References 94 publications

(149 reference statements)

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“…In addition, a recent study has shown that PRLR activation and downstream signalling by STAT5 results in quiescence of hair follicle stem cells during pregnancy and lactation. This study also remarked that STAT5 activation was present in the DP of non-pregnant, pregnant and lactating mice (Goldstein et al, 2014). These studies conclude that PRLR activation results in either quiescence or catagen induction within the hair follicle, which is contradictory to our proposed role of STAT5.…”

Section: Discussioncontrasting

confidence: 52%

“…Furthermore, these effects are described in hair follicle cycling during pregnancy and not during native hair cycling. Notably, the study showed localisation of activated STAT5 within the DP; however, this did not appear to be related to prolactin signalling (Goldstein et al, 2014).…”

Section: Introductionmentioning

confidence: 96%

“…Conversely, multiple studies describe PRLR expression within the hair follicle epidermal compartment, as well as the effects of prolactin on hair cycling. A recent study has described STAT5 as part of a PRLR signalling pathway that is responsible for quiescence of hair follicle stem cells during pregnancy and lactation (Goldstein et al, 2014). Furthermore, earlier studies have provided evidence to suggest that PRLR activation results in catagen induction or a significant delay in anagen entry (Craven et al, 2006;Foitzik et al, 2006;Foitzik et al, 2003).…”

Section: Stat5 and The Dermal Papilla Control Of Hair Cyclingmentioning

confidence: 99%

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Mesenchymal-epidermal interactions in hair follicle cycling and regeneration

Legrand¹

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The hair follicle is an important skin appendage that arises during development from complex reciprocal signalling between the epidermis and dermis. The multiple epidermal layers of the hair follicle are known to be under the control of the mesenchymal component, the dermal papilla (DP), which has been described as the key regulator of hair follicle induction and maintenance. The hair follicle has elicited interest as a model system for the investigation of tissue and organ regeneration due to its ability to regenerate completely throughout the life of a mammal. This characteristic is attributed to the reservoir of stem cells within the hair follicle, which is modulated by the DP.Although it is known that the DP is central to regulation of the hair follicle, mediators of its signalling are incompletely understood. Potential mediators of DP activity continue to emerge, two of which include the SoxF transcription factor, Sox18, and the transcription factor, STAT5. Sox18 has been implicated in hair type specification by the DP; however, its expression and function remains unclear. STAT5 has been shown in microarray analyses of the DP to be specifically expressed and upregulated, while studies involving STAT5 genetic knockouts display a hair phenotype. More recently, STAT5 has been implicated in autoimmune conditions affecting the hair follicle such as alopecia areata.To investigate further the role of STAT5 in the DP, I have hypothesised that STAT5 plays a key role in the DP's hair follicle inductive properties and regulation of cycling.STAT5 activation in the DP was characterised through immunofluorescence staining of mouse back skin at various stages of hair follicle development and cycling. Back skin was obtained from Topflash transgenic mice, a canonical Wnt reporter transgenic mouse driving luciferase expression, using β-catenin activity to monitor hair cycling via live bioluminescence imaging. While embryonic skin did not display any activation of STAT5, during postnatal hair follicle development (P0-P19), the majority of phospho-STAT5 positive DP were present within telogen phase, to a lesser extent within catagen and not at all during anagen. Adult skin showed phospho-STAT5 activation beginning in late catagen and persisting through to early anagen.Characterisation of SOCS2 by immunofluorescence, a downstream STAT5 transcriptional target, showed expression corresponding to the chronology of phospho-STAT5 activity.Hair regeneration assays were performed with DP cells using SKP culture with STAT5 activity modified through adenovirus constructs. SKPs derived from C57BL/6 neonates and STAT5 lox/lox neonates were transduced with STAT5A/B constitutively-active and crerecombinase constructs, respectively. These transduced SKPs were then used in patch assay experiments and DP formation was quantified using a green fluorescent protein ii (GFP) reporter. SKPs transduced with constitutively-active STAT5 were significantly better at forming hair follicle DP than control SKPs transduced with GFP alone. SKPs with...

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Section: Discussioncontrasting

confidence: 52%

Section: Introductionmentioning

confidence: 96%

Section: Stat5 and The Dermal Papilla Control Of Hair Cyclingmentioning

confidence: 99%

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Mesenchymal-epidermal interactions in hair follicle cycling and regeneration

Legrand¹

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“…Shaving adult rodents induces the shift from telogen (resting phase) to anagen (i.e., growing phase). In such models, PRL was shown to exert an inhibitory role on hair regrowth, which was recently proposed to involve the maintenance of hair follicle stem cells in quiescence [81]. Accordingly, the Bayer neutralizing PRLR antibody was shown to stimulate hair regrowth after shaving hyper-and normo-prolactinemic male and female mice [23].…”

Section: Non-tumor Indications 451 Hair Lossmentioning

confidence: 99%

The prolactin receptor as a therapeutic target in human diseases: browsing new potential indications

Goffin

Touraine

2015

Expert Opinion on Therapeutic Targets

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“…EpSCs and their daughter cells, which are also known as keratinocytes, play an essential role in re-epithelialization by first migrating from their niche towards the wound and then undergoing proliferation and differentiation. Previous studies have shown that biological processes, such as pregnancy, lactation [14, 15], hypoxia [16] and circadian rhythms [17], can impact stem cells. In this study, we focused on how EpSCs respond to hypoxia.…”

Section: Introductionmentioning

confidence: 99%

FG-4592 Accelerates Cutaneous Wound Healing by Epidermal Stem Cell Activation via HIF-1α Stabilization

Tang

Zhang

Yan

et al. 2018

Cell Physiol Biochem

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Background/Aims: Regional hypoxia promptly develops after trauma because of microvascular injury and increased oxygen consumption. This acute hypoxia plays a positive role in early skin wound healing. One of the mechanisms underlying the beneficial effects of acute hypoxia on wound healing may be increased hypoxia-inducible factor-1 (HIF-1α) expression. HIF-1α may affect the wound-healing process through many aspects, including angiogenesis, metabolism, and extra-cellular matrix synthesis and remodelling. Epidermal stem cells (EpSCs) are important participants in wound repair; however, whether these cells are regulated by hypoxia is unclear. This study aimed to elucidate the regulatory mechanism by which hypoxia acts on EpSCs. Methods: CCK8 assays, western blots and live cell station observation were employed to compare the viability, proliferation and motility of EpSCs cultured under normoxic conditions (21% O₂) with those cultured under hypoxic conditions (2% O₂). Moreover, we used FG-4592 (a prolyl hydroxylase inhibitor that stabilizes HIF-1α in normoxia), KC7F2 (a selective inhibitor of HIF-1α transcription) and siRNA against HIF-1α to regulate HIF-1α expression. Results: Acute hypoxia caused EpSCs to switch from a quiescent state to an activated state with higher viability and motility, as well as an earlier proliferation peak. We demonstrated that the HIF-1 signalling pathway mediated hypoxia-induced activation of EpSCs. Finally, the in vivo experiments showed that exogenous FG-4592 effectively accelerates wound healing, shortens healing times and even induces epidermal hyperplasia. Conclusion: This study demonstrated that both hypoxia and exogenous FG-4592 improve EpSC proliferation and motility by stabilizing HIF-1α, and its results suggest that HIF-1α is an important target through which wound healing can be accelerated and that FG-4592 is a promising new drug for wound repair.

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

Cited by 43 publications

References 94 publications

Mesenchymal-epidermal interactions in hair follicle cycling and regeneration

Mesenchymal-epidermal interactions in hair follicle cycling and regeneration

The prolactin receptor as a therapeutic target in human diseases: browsing new potential indications

FG-4592 Accelerates Cutaneous Wound Healing by Epidermal Stem Cell Activation via HIF-1α Stabilization

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