An Extended Epidermal Response Heals Cutaneous Wounds in the Absence of a Hair Follicle Stem Cell Contribution

Faculty of Life Sciences, University of Manchester, Manchester, UK.
Journal of Investigative Dermatology (Impact Factor: 7.22). 06/2008; 128(5):1311-8. DOI: 10.1038/sj.jid.5701178
Source: PubMed


Hair follicles have been observed to provide a major cellular contribution to epidermal healing, with emigration of stem-derived cells from the follicles aiding in wound reepithelialization. However, the functional requirements for this hair follicle input are unknown. Here we have characterized the keratinocyte stem cell status of mutant mice that lack all hair follicle development on their tail, and analyzed the consequent alterations in epidermal wound healing rate and mechanisms. In analyzing stem cell behavior in embryonic skin we found that clonogenic keratinocytes are relatively frequent in the ectoderm prior to hair follicle formation. However, their frequency in the interfollicular epidermis drops sharply by birth, at which time the majority of stem cells are present within the hair follicles. We find that in the absence of hair follicles cutaneous wounds heal with an acute delay in reepithelialization. This delay is followed by expansion of the region of activated epidermis, beyond that seen in normal haired skin, followed by appropriate wound closure. JID Journal Club article: for questions, answers, and open discussion about this article please go to

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    • "The fact that PSU-derived cells are detected within the IFE shortly after injury suggests that normal boundaries between the PSU and the IFE do not prohibit cell migration and mixing between compartments following injury (Nowak et al., 2008; Levy et al., 2007). In contrast to full-thickness wounding, cells from within the PSU are not required for tissue repair following incisional wounds in the tail epithelium (Langton et al., 2008), and lineage-tracing data show that IFE-derived progeny in general are a major source for regeneration in response to a small biopsy on the tail (Mascre et al., 2012). It is therefore clear that the severity of the initial trauma greatly influences the regenerative process and the cellular response. "
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    ABSTRACT: The epidermis is an integral part of our largest organ, the skin, and protects us against the hostile environment. It is a highly dynamic tissue that, during normal steady-state conditions, undergoes constant turnover. Multiple stem cell populations residing in autonomously maintained compartments facilitate this task. In this Review, we discuss stem cell behaviour during normal tissue homeostasis, regeneration and disease within the pilosebaceous unit, an integral structure of the epidermis that is responsible for hair growth and lubrication of the epithelium. We provide an up-to-date view of the pilosebaceous unit, encompassing the heterogeneity and plasticity of multiple discrete stem cell populations that are strongly influenced by external cues to maintain their identity and function.
    Development 07/2014; 141(13):2559-2567. DOI:10.1242/dev.104588 · 6.46 Impact Factor
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    • "Using an ear wound model, we demonstrate a similar result: full thickness injuries created during anagen completely heal, while those created during telogen do not. A number of explanations have been put forth: keratinocytes derived from adnexal structures are known to contribute to wound healing [13], [37] and during anagen, wounds may re-epithelialize faster because of this increase in keratinocyte proliferation [25]. A reduction in inflammatory cell infiltration has also been described, which may contribute to faster wound healing (reviewed in [38]. "
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    ABSTRACT: Wnt signaling is required for both the development and homeostasis of the skin, yet its contribution to skin wound repair remains controversial. By employing Axin2(LacZ/+) reporter mice we evaluated the spatial and temporal distribution patterns of Wnt responsive cells, and found that the pattern of Wnt responsiveness varies with the hair cycle, and correlates with wound healing potential. Using Axin2(LacZ/LacZ) mice and an ear wound model, we demonstrate that amplified Wnt signaling leads to improved healing. Utilizing a biochemical approach that mimics the amplified Wnt response of Axin2(LacZ/LacZ) mice, we show that topical application of liposomal Wnt3a to a non-healing wound enhances endogenous Wnt signaling, and results in better skin wound healing. Given the importance of Wnt signaling in the maintenance and repair of skin, liposomal Wnt3a may have widespread application in clinical practice.
    PLoS ONE 10/2013; 8(10):e76883. DOI:10.1371/journal.pone.0076883 · 3.23 Impact Factor
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    • "Compartmentalization IFE SCs have been shown to be the major contributor to tissue regeneration following injury (Mascré et al., 2012); however, evidence from hairless mice and lineage tracing from pilosebaceous SCs supports a role for these cells in the regenerative response (Brownell et al., 2011; Ito et al., 2005; Langton et al., 2008; Snippert et al., 2010). It has also not been clear to what extent cells were specifically retained in the IFE following tissue repair based on their ancestry (Plikus et al., 2012). "
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    ABSTRACT: The complex anatomy of the epidermis contains multiple adult stem cell populations, but the extent to which they functionally overlap during homeostasis, wound healing, and tumor initiation remains poorly defined. Here, we demonstrate that Lrig1(+ve) cells are highly proliferative epidermal stem cells. Long-term clonal analysis reveals that Lrig1(+ve) cells maintain the upper pilosebaceous unit, containing the infundibulum and sebaceous gland as independent compartments, but contribute to neither the hair follicle nor the interfollicular epidermis, which are maintained by distinct stem cell populations. In contrast, upon wounding, stem cell progeny from multiple compartments acquire lineage plasticity and make permanent contributions to regenerating tissue. We further show that oncogene activation in Lrig1(+ve) cells drives hyperplasia but requires auxiliary stimuli for tumor formation. In summary, our data demonstrate that epidermal stem cells are lineage restricted during homeostasis and suggest that compartmentalization may constitute a conserved mechanism underlying epithelial tissue maintenance.
    Cell stem cell 08/2013; 13(4). DOI:10.1016/j.stem.2013.07.010 · 22.27 Impact Factor
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