Interfollicular epidermal homeostasis: dicing with differentiation.
TL;DR: It is revealed that the epidermis is maintained by a single population of functionally equivalent cycling progenitor cells, and is placed in the context of other tissues that are also maintained by continually cycling cells with stochastic fate.
Abstract: In the 1970s, studies of tissue architecture and cell proliferation were used to formulate a new model of epidermal homeostasis. This asserted that the tissue was maintained by long-lived, slow-cycling, self-renewing stem cells that generate a short-lived population of transit amplifying (TA) cells, which undergo terminal differentiation after a set number of cell divisions. It was further hypothesized that in the epidermis, the tissue was organized into clonal epidermal proliferative units (EPUs) comprising a central stem cell with surrounding TA cells, which maintain the overlying differentiated cell layers. The stem/TA and EPU hypotheses have been widely influential. Here, we first revaluate older literature, finding numerous studies that conflict with the EPU model. We then review recent large-scale lineage tracing studies in transgenic mice which exclude the stem/TA and EPU hypotheses, and reveal that the epidermis is maintained by a single population of functionally equivalent cycling progenitor cells. The outcome of individual progenitor cell divisions is random, but the probabilities of generating differentiated and progenitor cell daughters are equal, so that homeostasis is maintained across the progenitor population. We reconcile this model with the older literature and place the epidermis in the context of other tissues that are also maintained by continually cycling cells with stochastic fate.
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TL;DR: It is shown that changes in the microenvironment including alterations in mechanical forces, oxygen levels, chemokines, extracellular matrix and growth factor synthesis directly impact cellular recruitment and activation, leading to impaired states of wound healing.
Abstract: Wound healing is one of the most complex processes in the human body. It involves the spatial and temporal synchronization of a variety of cell types with distinct roles in the phases of hemostasis...
1,018 citations
Cites background from "Interfollicular epidermal homeostas..."
...An alternative theory suggests that there are no IFE stem cells; instead, all cells in the basal layer are functionally equivalent progenitor cells with equal probabilities of generating a differentiated cell or a progenitor cell (91, 236)....
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TL;DR: The pivotal role of keratinocytes in epithelialization is focused on, including cellular processes and mechanisms of their regulation during re-epithelialization, and their cross talk with other cell types participating in wound healing.
Abstract: Significance: Keratinocytes, a major cellular component of the epidermis, are responsible for restoring the epidermis after injury through a process termed epithelialization. This review will focus on the pivotal role of keratinocytes in epithelialization, including cellular processes and mechanisms of their regulation during re-epithelialization, and their cross talk with other cell types participating in wound healing. Recent Advances: Discoveries in epidermal stem cells, keratinocyte immune function, and the role of the epidermis as an independent neuroendocrine organ will be reviewed. Novel mechanisms of gene expression regulation important for re-epithelialization, including microRNAs and histone modifications, will also be discussed. Critical Issues: Epithelialization is an essential component of wound healing used as a defining parameter of a successful wound closure. A wound cannot be considered healed in the absence of re-epithelialization. The epithelialization process is impaired in all types o...
914 citations
TL;DR: It is shown that COL17 plays a central role in regulating interfollicular epidermis (IFE) proliferation and could be an important target of anti-aging strategies in the skin.
Abstract: Type XVII collagen (COL17) is a transmembrane protein located at the epidermal basement membrane zone. COL17 deficiency results in premature hair aging phenotypes and in junctional epidermolysis bullosa. Here, we show that COL17 plays a central role in regulating interfollicular epidermis (IFE) proliferation. Loss of COL17 leads to transient IFE hypertrophy in neonatal mice owing to aberrant Wnt signaling. The replenishment of COL17 in the neonatal epidermis of COL17-null mice reverses the proliferative IFE phenotype and the altered Wnt signaling. Physical aging abolishes membranous COL17 in IFE basal cells because of inactive atypical protein kinase C signaling and also induces epidermal hyperproliferation. The overexpression of human COL17 in aged mouse epidermis suppresses IFE hypertrophy. These findings demonstrate that COL17 governs IFE proliferation of neonatal and aged skin in distinct ways. Our study indicates that COL17 could be an important target of anti-aging strategies in the skin.
90 citations
TL;DR: The results elucidate the interrelation and behavior of Lgr6+ populations in the IFE, HF, and SG and suggest population asymmetry as a common mechanism for homeostasis in several epithelial skin compartments.
Abstract: The dynamics and interactions between stem cell pools in the hair follicle (HF), sebaceous gland (SG), and interfollicular epidermis (IFE) of murine skin are still poorly understood. In this study, we used multicolor lineage tracing to mark Lgr6-expressing basal cells in the HF isthmus, SG, and IFE. We show that these Lgr6+ cells constitute long-term self-renewing populations within each compartment in adult skin. Quantitative analysis of clonal dynamics revealed that the Lgr6+ progenitor cells compete neutrally in the IFE, isthmus, and SG, indicating population asymmetry as the underlying mode of tissue renewal. Transcriptional profiling of Lgr6+ and Lgr6− cells did not reveal a distinct Lgr6-associated gene expression signature, raising the question of whether Lgr6 expression requires extrinsic niche signals. Our results elucidate the interrelation and behavior of Lgr6+ populations in the IFE, HF, and SG and suggest population asymmetry as a common mechanism for homeostasis in several epithelial skin compartments.
83 citations
Cites background from "Interfollicular epidermal homeostas..."
...However, the mode of stem cell renewal in the IFE has been a subject of intense research (Doupé and Jones, 2012)....
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...However, the mode of stem cell renewal in the IFE has been a subject of intense research (Doupé and Jones, 2012)....
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TL;DR: The relevance of Notch1 signaling, gap-junction formation, HIF-1α and metabolic state in the regulation of stem cell growth and differentiation within the cardiac niches are discussed.
74 citations
Cites background from "Interfollicular epidermal homeostas..."
...…cells defines the growth reserve of the organ and its ability to regulate tissue homeostasis and promote the structural recover following injury (Doupé and Jones, 2012; Ihrie and Alvarez-Buylla, 2011) Activation of the Notch1 pathway favors the commitment of CSCs to the myocyte lineage and…...
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...In stem cell-regulated organs, the pool size of transient amplifying cells defines the growth reserve of the organ and its ability to regulate tissue homeostasis and promote the structural recover following injury (Doupé and Jones, 2012; Ihrie and Alvarez-Buylla, 2011) Activation of the Notch1 pathway favors the commitment of CSCs to the myocyte lineage and controls the size of the compartment of replicating myocytes in vitro and in vivo....
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Book•
01 Jan 1984
TL;DR: Volume 2 covers cell renewal and organization in the gastrointestinal epithelia, and the conditional renewal populations.
Abstract: Volume 2 covers cell renewal and organization in the gastrointestinal epithelia, and the conditional renewal populations.
405 citations