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Hair follicle stem cell compartments. Different stem cell populations are shown in the mouse resting (telogen) adult hair follicle. Each stem cell compartment is defined by distinct protein expression and gene promoter activity (see key); cells with multiple colours express multiple markers.
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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 st...
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... initiate terminal differentiation and, following extensive remodelling of intracellular proteins, intercellular junctions, lipid extrusion and nuclear fragmentation, the cells eventually become highly cross-linked scales that are exfoliated from the surface of the skin. The pilosebaceous unit (PSU) is a prominent structure associated with the IFE (Fig. 1). It has important functions within the tissue that are mediated via its components: infundibulum, isthmus, sebaceous glands and the hair follicle. The infundibulum forms the upper part of the PSU between the IFE and the isthmus. The isthmus forms the mid-region starting at the top of the bulge and ending at the infundibulum, where it ...
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... isthmus, sebaceous glands and the hair follicle. The infundibulum forms the upper part of the PSU between the IFE and the isthmus. The isthmus forms the mid-region starting at the top of the bulge and ending at the infundibulum, where it segregates hair follicle and interfollicular differentiation markers and creates a funnel for the hair shaft (Fig. 1). The upper region of the isthmus adjacent to the infundibulum and the sebaceous gland is defined as the junctional zone (JZ) ). The sebaceous gland produces sebum, an antiseptic oily substance that lubricates the hair and the surface of the skin. Similar to the IFE, proliferating cells in the sebaceous gland anchored to the basement ...
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... support turnover of differentiated cells as they burst and release their lipid content. The lower, permanent PSU can be divided into two parts: the bulge and the hair germ. Hair follicle stem cells reside in the bulge, whereas the hair germ is located directly above the dermal papilla and forms the germinal centre for hair follicle growth ( Fig. 1) (Silver and Chase, ...
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... phase and a long telogen phase at ∼P42-49, which lasts 2-3 weeks ( Alonso and Fuchs, 2006). Subsequent hair cycles of individual follicles are then asynchronous and are instructed by local signals ( ). The cyclic nature of this process is governed by an intricate interplay between dermal cells and epidermal keratinocytes in the lower PSU ( Fig. 1) Driskell et al., 2009;Greco et al., ...
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... cellular heterogeneity exists within the mature PSU and this has been the topic of a number of excellent recent reviews (Arwert et al., 2012;Rompolas and Greco, 2014;Solanas and Benitah, 2013). Several different populations of cells have been shown to maintain the PSU, and are characterised by the expression of a variety of different markers (see Fig. 1). These include: Lgr5, CD34 and Krt15, which mark the hair follicle bulge stem cells ( Liu et al., 2003;Trempus et al., 2003;Jaks et al., 2008); Blimp1 (Prdm1), which marks the sebaceous gland stem cells (Horsley et al., 2006); Gli1 and Lgr6, which mark stem cells in the lower isthmus (Snippert et al., 2010;Brownell et al., 2011); and ...
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... best-characterised stem cell population in the PSU resides in the bulge region (bulge stem cells; Fig. 1). These cells have been the focus of numerous investigations because of their prominent location, highly quiescent nature ( Cotsarelis et al., 1990), extensive clonogenic capacity in vitro ( Oshima et al., 2001) and their expression of a set of distinct markers (reviewed by Fuchs and Horsley, 2008). Bulge stem cells were initially ...
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The skin has important barrier, sensory, and immune functions, contributing to the health and integrity of the organism. Extensive skin injuries that threaten the entire organism require immediate and effective treatment. Wound healing is a natural response, but in severe conditions, such as burns and diabetes, this process is insufficient to achie...
Citations
... The maintenance of the epidermis throughout life involves the proliferation of stem cells and the differentiation of their progeny. Various epithelial stem cell (SC) populations contribute to skin homeostasis, and among them, the most characterized is the Hair Follicle Stem Cells (HFSCs) which is located in the permanent portion of the hair follicle, ranging from the bulge to the junctional zone (Schepeler et al., 2014). ...
Adult stem cells play a critical role in maintaining tissue homeostasis and promoting longevity. The intricate organization and presence of common markers among adult epithelial stem cells in the intestine, lung, and skin serve as hallmarks of these cells. The specific location pattern of these cells within their respective organs highlights the significance of the niche in which they reside. The extracellular matrix (ECM) not only provides physical support but also acts as a reservoir for various biochemical and biophysical signals. We will consider differences in proliferation, repair, and regenerative capacities of the three epithelia and review how environmental cues emerging from the niche regulate cell fate. These cues are transduced via mechanosignaling, regulating gene expression, and bring us to the concept of the fate scaffold. Understanding both the analogies and discrepancies in the mechanisms that govern stem cell fate in various organs can offer valuable insights for rejuvenation therapy and tissue engineering.
... The newly formed wound stroma serves as a framework for wound re-epithelialization. The sources of new keratinocyte formation are stem cells of the basal layer of the epidermis, epitheliocytes of the outlet streams of sweat and sebaceous glands, and epitheliocytes of hair follicles [5]. These cells are ascribed stem cell (SC) properties. ...
Abstract
A characteristic feature of repair processes in mammals is the formation of scar tissue at the site of injury, which is designed to quickly prevent contact between the internal environment of the organism and the external environment. Despite this general pattern, different organs differ in the degree of severity of scar changes in response to injury. One of the areas in which regeneration after wounding leads to the formation of a structure close to the original one is the abdominal skin of laboratory rats. Finding out the reasons for such a phenomenon is essential for the development of ways to stimulate full regeneration. The model of skin wound healing in the abdominal region of laboratory animals was reproduced in this work. It was found that the wound surface is completely epithelialized on the abdomen by 20 days, while on the back—by 30 days. The qPCR method revealed higher expression of marker genes of skin stem cells (Sox9, Lgr6, Gli1, Lrig1) in the intact skin of the abdomen compared to the back, which corresponded to a greater number of hairs with which stem cells are associated on the abdomen compared to the back. Considering that some stem cell populations are associated with hair, it can be suggested that one of the factors in faster regeneration of abdominal skin in the rat is the greater number of stem cells in this area.
... Introduction Cellular heterogeneity underlies all biological systems. Heterogeneity exists across the varying stages of development, differentiation, and disease over length scales from DNA to organism [1][2][3]. This cellular heterogeneity emerges as a result of epigenetic, transcriptional, and posttranslational diversity within and between populations [4,5]. ...
Numerous techniques have been employed to deconstruct the heterogeneity observed in normal and diseased cellular populations, including single cell RNA sequencing, in situ hybridization, and flow cytometry. While these approaches have revolutionized our understanding of heterogeneity, in isolation they cannot correlate phenotypic information within a physiologically relevant live-cell state with molecular profiles. This inability to integrate a live-cell phenotype—such as invasiveness, cell:cell interactions, and changes in spatial positioning—with multi-omic data creates a gap in understanding cellular heterogeneity. We sought to address this gap by employing lab technologies to design a detailed protocol, termed Spatiotemporal Genomic and Cellular Analysis (SaGA), for the precise imaging-based selection, isolation, and expansion of phenotypically distinct live cells. This protocol requires cells expressing a photoconvertible fluorescent protein and employs live cell confocal microscopy to photoconvert a user-defined single cell or set of cells displaying a phenotype of interest. The total population is then extracted from its microenvironment, and the optically highlighted cells are isolated using fluorescence activated cell sorting. SaGA-isolated cells can then be subjected to multi-omics analysis or cellular propagation for in vitro or in vivo studies. This protocol can be applied to a variety of conditions, creating protocol flexibility for user-specific research interests. The SaGA technique can be accomplished in one workday by non-specialists and results in a phenotypically defined cellular subpopulations for integration with multi-omics techniques. We envision this approach providing multi-dimensional datasets exploring the relationship between live cell phenotypes and multi-omic heterogeneity within normal and diseased cellular populations.
... In deep burned patients which have lost the skin coverage, the epidermis can reform provided that the hair bulges were not affected. Regardless of this, some authors, based on a careful characterization of cells in the adult mouse hair follicle, suggested the existence of different SC populations located in different regions of the hair follicle and defined by distinct protein expression and gene promoter activity (Schepeler et al., 2014). In our opinion, while we are still searching for specific markers to distinguish between SCs and TACs, the identification and definition of different SC populations and TACs could be seen more as a semantic matter than a real distinction between true SCs and their progeny. ...
Maintenance of tissue homeostasis and tissue regeneration after an insult are essential functions of adult stem cells (SCs). In adult tissues, SCs proliferate at a very slow rate within “stem cell niches”, but, during tissue development and regeneration, before giving rise to differentiated cells, they give rise to multipotent and highly proliferative cells, known as transit-amplifying cells (TACs). Although differences exist in diverse tissues, TACs are not only a transitory phase from SCs to post-mitotic cells, but they also actively control proliferation and number of their ancestor SCs and proliferation and differentiation of their progeny toward tissue specific functional cells. Autocrine signals and negative and positive feedback and feedforward paracrine signals play a major role in these controls. In the present review we will consider the generation and the role played by TACs during development and regeneration of lining epithelia characterized by a high turnover including epidermis and hair follicles, ocular epithelial surfaces, and intestinal mucosa. A comparison between these different tissues will be made. There are some genes and molecular pathways whose expression and activation are common to most TACs regardless their tissue of origin. These include, among others, Wnt, Notch, Hedgehog and BMP pathways. However, the response to these molecular signals can vary in TACs of different tissues. Secondly, we will consider cultured cells derived from tissues of mesodermal origin and widely adopted for cell therapy treatments. These include mesenchymal stem cells and dedifferentiated chondrocytes. The possible correlation between cell dedifferentiation and reversion to a transit amplifying cell stage will be discussed.
... Second, when the SG stem cell niche is perturbed, either by wounding or genetic ablation, alternative stem cells rapidly enter the SG domain to repopulate the gland. These findings are consistent with the view that stem cells within discrete hair follicle niches serve largely compartmentalized roles during homeostasis, but become highly plastic following injury (Han et al., 2023;Huang et al., 2020;Schepeler et al., 2014). ...
Sebaceous glands (SGs) release oils that protect our skin, but how these glands respond to injury has not been previously examined. Here, we report that SGs are largely self-renewed by dedicated stem cell pools during homeostasis. Using targeted single cell RNA-sequencing, we uncovered both direct and indirect paths by which these resident SG progenitors ordinarily differentiate into sebocytes, including transit through a PPARgamma+Krt5+ transitional cell state. Upon skin injury, however, SG progenitors depart their niche, reepithelialize the wound, and are replaced by hair follicle-derived stem cells. Furthermore, following targeted genetic ablation of >99% of SGs from dorsal skin, these glands unexpectedly regenerate within weeks. This regenerative process is mediated by alternative stem cells originating from the hair follicle bulge, is dependent upon FGFR signaling, and can be accelerated by inducing hair growth. Altogether, our studies demonstrate that stem cell plasticity promotes SG durability following injury.
... Cellular heterogeneity underlies all biological systems. Heterogeneity exists across the varying stages of development, differentiation, and disease over length scales from DNA to organism [1][2][3] . This cellular heterogeneity emerges as a result of epigenetic, transcriptional, and post-translational diversity within and between populations 4,5 . ...
... Timing 1 h (thawing cells), 1 week (cell growth and maintenance)1. Prepare cell culture media as described in reagent set up.2. ...
Numerous techniques have been employed to deconstruct the heterogeneity observed in normal and diseased cellular populations, including single cell RNA sequencing, in situ hybridization, and flow cytometry. While these approaches have revolutionized our understanding of heterogeneity, in isolation they cannot correlate phenotypic information within a physiologically relevant live-cell state, with molecular profiles. This inability to integrate a historical live-cell phenotype, such as invasiveness, cell:cell interactions, and changes in spatial positioning, with multi-omic data, creates a gap in understanding cellular heterogeneity. We sought to address this gap by employing lab technologies to design a detailed protocol, termed Spatiotemporal Genomics and Cellular Analysis (SaGA), for the precise imaging-based selection, isolation, and expansion of phenotypically distinct live-cells. We begin with cells stably expressing a photoconvertible fluorescent protein and employ live cell confocal microscopy to photoconvert a user-defined single cell or set of cells displaying a phenotype of interest. The total population is then extracted from its microenvironment, and the optically highlighted cells are isolated using fluorescence activated cell sorting. SaGA-isolated cells can then be subjected to multi-omics analysis or cellular propagation for in vitro or in vivo studies. This protocol can be applied to a variety of conditions, creating protocol flexibility for user-specific research interests. The SaGA technique can be accomplished in one workday by non-specialists and results in a phenotypically defined cellular subpopulation for integration with multi-omics techniques. We envision this approach providing multi-dimensional datasets exploring the relationship between live-cell phenotype and multi-omic heterogeneity within normal and diseased cellular populations.
... HFs are morphologically and histologically complex mini-organs, which pass through regular cycles of growth (anagen), regression (catagen), and rest (telogen) to maintain the mammalian hair coat (for reviews, see Müller-Röver et al. 2001;Schmidt-Ullrich and Paus 2005;Alonso and Fuchs 2006). The combination of gene-specific reporter mice and genetic lineage tracing has revealed a surprising variety of stem cell populations in the telogen HF ( Fig. 1C; for reviews, see Jaks et al. 2010;Kretzschmar and Watt 2014;Rompolas and Greco 2014;Schepeler et al. 2014;Gonzales and Fuchs 2017;Belokhvostova et al. 2018;Dekoninck and Blanpain 2019). These distinct stem cell populations locally maintain the infundibulum, junctional zone, isthmus, sebaceous gland, and the bulge region of the HF. ...
Epithelial tissues line the outer surfaces of the mammalian body and protect from external harm. In skin, the epithelium is maintained by distinct stem cell populations residing in the interfollicular epidermis and various niches of the hair follicle. These stem cells give rise to the stratified epidermal layers and the protective hair coat, while being confined to their respective niches. Upon injury, however, all stem cell progenies can leave their niche and collectively contribute to a central wound healing process, called reepithelialization, for restoring the skin's barrier function. This review explores how epithelial cells from distinct niches respond and adapt during acute wound repair. We discuss when and where cells sense and react to damage, how cellular identity is regulated at the molecular and behavioral level, and how cells memorize past experiences and their origin. This collective knowledge highlights cellular plasticity as a brilliant feature of epithelial tissues to heal.
... * Hongwei Liu liuhongwei0521@hotmail.com * Xuejuan Xu xxj@fsyyy.com epithelial cells, adult stem cells show remarkable heterogeneity and plasticity under a particular physiological or pathological condition [4,5]. The epidermis functions as a protective barrier for the body and is crucial in protecting against hostile environment and retaining bodily fluids inside [6]. ...
... The epidermis and its appendages developed from multipotent embryonic progenitor keratinocytes, which receive cues from their environment that instruct them to commit to a certain differentiation programme and generate a stratified epidermis, hair follicles or sebaceous glands [10].The epidermis and its appendages are a highly dynamic tissue that undergoes constant turnover during normal steady-state conditions [11,12]. Multiple stem cell populations residing in autonomously maintained compartments facilitate this task [4,13]. Epidermal stem cells (EpSCs) locate in different niches have their own markers and functions [14]. ...
... EpSCs have been studied for possible proliferative potential since the 1970 s to form stratified squamous epithelium with more advanced keratinisation by epithelial cells from human skin biopsies [19]. Subsequently, cellular heterogeneity defined by marker expression, cell division rate and ultrastructure, has been studied both in IFE and PSU [4]. ...
Cellular differentiation, the fundamental hallmark of cells, plays a critical role in homeostasis. And stem cells not only regulate the process where embryonic stem cells develop into a complete organism, but also replace ageing or damaged cells by proliferation, differentiation and migration. In characterizing distinct subpopulations of skin epithelial cells, stem cells show large heterogeneity and plasticity for homeostasis, wound healing and tumorigenesis. Epithelial stem cells and committed progenitors replenish each other or by themselves owing to the remarkable plasticity and heterogeneity of epidermal cells under certain circumstance. The development of new assay methods, including single-cell RNA sequence, lineage tracing assay, intravital microscopy systems and photon-ablation assay, highlight the plasticity of epidermal stem cells in response to injure and tumorigenesis. However, the critical mechanisms and key factors that regulate cellular plasticity still need for further exploration. In this review, we discuss the recent insights about the heterogeneity and plasticity of epithelial stem cells in homeostasis, wound healing and skin tumorigenesis. Understanding how stem cells collaborate together to repair injury and initiate tumor will offer new solutions for relevant diseases.
Graphical Abstract
Schematic abstract of cellular heterogeneity and plasticity of skin epithelial cells in wound healing and tumorigenesis
... 1 The SCs responsible for cyclic HF regeneration are located in the permanent non-cyclic HF portion called the bulge 1,15,16 (Figure 1). The upper portion of the HF does not cycle but turns over frequently, which is governed by multiple resident SC pools [15][16][17] (Figure 1). The identity, organization and dynamics of SCs within the IFE are still matters of debate. ...
Skin cancers are by far the most frequently diagnosed human cancers. The closely related transcriptional co‐regulator proteins YAP and TAZ (WWTR1) have emerged as important drivers of tumor initiation, progression and metastasis in melanoma and non‐melanoma skin cancers. YAP/TAZ serve as an essential signaling hub by integrating signals from multiple upstream pathways. In this review, we summarize the roles of YAP/TAZ in skin physiology and tumorigenesis and discuss recent efforts of therapeutic interventions that target YAP/TAZ in in both preclinical and clinical settings, as well as their prospects for use as skin cancer treatments.
... arrector pili and the duct of the sebaceous gland. The population of these cells is quite plastic, but varies in the level of maturity, proliferative activity and tendency to differentiate in the direction of certain skin cells [79]. Epidermal stem cells of the neural crest are the most promising: they can give rise to bone/cartilage cells, neurons, Schwann cells, myofibroblasts, and melanocytes [80]. ...
Article represents relevant classification of human stem cells with comparative characteristics of their subtypes
