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. 2023 May;15(5):a041232. doi: 10.1101/cshperspect.a041232

Plasticity of Epithelial Cells during Skin Wound Healing

Xiaoyan Sun 1,✉, Simon Joost 2, Maria Kasper 1,✉
PMCID: PMC10153802  PMID: 36376081

Abstract

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.

The epidermis is the outer epithelial lining of the skin, acting as the first barrier of defense from external harm such as ultraviolet (UV) radiation or pathogens. In mice, the epidermis consists of two main compartments with distinct physiological functions: the interfollicular epidermis (IFE), and the hair follicles (HFs) with their associated sebaceous glands, which are embedded in a cell-type-rich dermis and hypodermis (Fig. 1A; Joost et al. 2020, for reviews, see Niemann and Watt 2002; Arwert et al. 2012; Hsu et al. 2014).

Figure 1.

Figure 1.

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Heterogeneity of epithelial cells in homeostatic mouse skin. (A) Microanatomy of telogen mouse skin. The epidermis consists of interfollicular epidermis (IFE) and hair follicles (HFs) (with associated sebaceous glands), which are embedded in a cell-type-rich dermis and hypodermis. (B) IFE cell layers and differentiation program. Classically, the IFE has been divided into basal, spinous, granular, and cornified layers that undergo a stepwise differentiation program. Recent scRNA-seq and intravital imaging revealed the IFE differentiation as a gradual process (Lin et al. 2020; Cockburn et al. 2021). (C) Cellular heterogeneity of the telogen HF based on previously described marker genes (left panel) or based on unbiased scRNA-seq analysis (right panel, classification based on Joost et al. 2016, 2020).

EPIDERMAL TISSUE MAINTENANCE AND CELLULAR HETEROGENEITY OF HEALTHY SKIN

The IFE is a squamous, stratified, multilayered epithelium, which creates and maintains the keratinized skin barrier by continuous proliferation, upward migration, and differentiation of keratinocytes. Based on histological and molecular features, the IFE is classically divided into four distinct layers: (1) the basal layer harboring the mitotically active stem cells, (2) the spinous layer receiving and transforming signals by desmosomes from neighboring cells, (3) the densely packed granular layer acting as water sealant, and (4) the stratum corneum made up by dead keratinocytes, which for example secrete defensins to provide a first immune defense for the mammalian body (Fig. 1B; for reviews, see Fuchs 1990, 2007; Hsu et al. 2014). The IFE is additionally interspersed with two abundant tissue-resident immune cell types, Langerhans cells (LCs) and γδ T cells known as dendritic epidermal T cells (DETCs) that sense damage and help maintain the epidermal barrier integrity (Fig. 1B; for reviews, see Jameson and Havran 2007; Deckers et al. 2018).

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. Right below the bulge, the hair germ cells are the first to be activated when a new hair cycle starts (Fig. 1A,C). Human skin and murine paws also harbor sweat glands, which are maintained by their own local stem and progenitor cells (Lu et al. 2012).

In recent years, single-cell RNA sequencing (scRNA-seq) analysis has provided comprehensive knowledge about the molecular and cellular heterogeneity defining cell types, subtypes, and cell states of the epidermis and its HFs in an unbiased, systematic fashion (e.g., Joost et al. 2016, 2020; Yang et al. 2017; Cheng et al. 2018; Haensel et al. 2020; Lin et al. 2020; Wang et al. 2020; Reynolds et al. 2021; for review, see Dubois et al. 2021). scRNA-seq-based studies revealed that the basal layer of the IFE is much more heterogeneous than previously thought (Joost et al. 2016, 2020; Haensel et al. 2020; Wang et al. 2020), and more recent work further demonstrated that IFE stratification is facilitated by continuous, gradual gene expression changes within and between the distinct layers (Fig. 1B; Lin et al. 2020; Cockburn et al. 2021). Notably, stem cell differentiation in the basal layer begins before morphological changes are visible and is uncoupled from the loss of proliferative capacity (Cockburn et al. 2021). The different compartments of the HF also harbor a great variety of keratinocyte populations (Fig. 1C). Interestingly, the cellular heterogeneity in HFs is predominantly shaped by a cell's differentiation status and its spatial location within the skin, and global transcriptional programs along the spatial axis (dermal papilla to IFE) change in a gradual fashion (Joost et al. 2016). Taken together, these new and detailed molecular insights from healthy skin suggest that transcriptional gradients—rather than discrete lineage boundaries—provide cells with the ability to quickly react, or even lineage-switch, in response to external damage such as an acute wound.

Wound healing in adult mammals is a vital mechanism to rebuild tissue following an injury, which is classically categorized into three overlapping stages: inflammation, proliferation, and remodeling. This choreographed process is conserved in most tissues, and depends on the continuous interplay of epithelial, mesenchymal, and immune cell types (for reviews, see Gurtner et al. 2008; Arwert et al. 2012). The process for restoring the wound epithelium is called reepithelialization. Cellular and molecular programs involved in the initiation, progression, and completion of reepithelialization are essential for successful wound closure, and failure in any of these stages can lead to impaired wound healing (e.g., chronic wounds or hypertrophic scars) (for review, see Chen et al. 2016). Thus, detailed molecular and behavioral understanding of epithelial cells in wound repair are crucial, and beg for answers to numerous intriguing questions. Do cells from all stem cell niches contribute to reepithelialization? When and where do cells from various niches sense and react to damage? How are changes in cellular identity regulated at a chromatin, transcriptional, and behavioral level? Do cells memorize what they have experienced and where they came from? In this review, we discuss current literature that sheds light on these questions, highlighting cellular plasticity as a brilliant feature of tissues to heal.

EPIDERMAL CELL BEHAVIOR, CONTRIBUTION, AND LINEAGE PLASTICITY DURING WOUND REPAIR

Upon skin injury, a multistep wound healing process is initiated that results in the recruitment of blood clotting factors, immune cells, fibroblasts, and other mesenchymal cells, culminating in the creation of granulation tissue at the wound site (for review, see Gurtner et al. 2008). The newly formed temporary fibrin extracellular matrix in early stages, and granulation tissue in later stages, serve as a scaffold for keratinocytes to migrate and reepithelialize the wound (Fig. 2A). For effective reepithelialization, distinct cellular behaviors need to be spatiotemporally coordinated and balanced. The wound-surrounding epithelial tissue is spatially patterned into a migratory leading edge closest to the wound, a proliferative zone behind the migratory leading edge and a mixed-interplay region between the two zones (Fig. 2B; Aragona et al. 2017; Park et al. 2017). The proliferative zone constantly supplies new cells for the migratory wound front, where cells of both basal and suprabasal layer undergo rapid migration and differentiation (Aragona et al. 2017; Park et al. 2017; for review, see Rognoni and Watt 2018).

Figure 2.

Figure 2.

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Epithelial cell contribution and cell behavior during wound repair. (A) Schematic of the multistep reepithelialization process, involving the activation of keratinocytes in early stage, proliferation and migration in intermediate stage, and complete wound closure and remodeling of epidermal barrier in late stage. (B) Illustration of the wound repairing epithelium. The wound-surrounding epithelial tissue is spatially divided into a migratory leading edge closest to the wound, a proliferative zone, and a “mixed” region between the two zones. Top panel shows a sagittal view. Lower panel shows a top view. (C) Contribution of lineage-traced Lgr5 hair follicle (HF) or Lgr6 interfollicular epidermis (IFE) stem cells during wound reepithelialization. Representative images of wounds taken 1, 3, 5, or 12 days post-wounding (dpw), show the temporospatial distribution of Lgr5- and Lgr6-progeny that have been labeled before wounding. (The right side in panel C is reprinted from Joost et al. 2018 under the terms of Creative Commons BY-NC-ND 4.0 license.) Dotted lines: approximate location of the basement membrane (thin) and wound front (thick). Filled lines: approximate location of the skin surface. (WF) Wound front. Scale bars, 100 μm. (D) Schematic overview of different injury types and corresponding major cellular contribution.

In contrast to skin homeostasis, stem cell progenies are not restricted to their original niches during wound healing (for reviews, see Arwert et al. 2012; Plikus et al. 2012; Dekoninck and Blanpain 2019). Not only the keratinocytes of the IFE but also cells from various HF compartments, the sebaceous glands, and sweat glands contribute to wound reepithelialization (Ito et al. 2005; Brownell et al. 2011; Page et al. 2013; Füllgrabe et al. 2015; Donati et al. 2017; Gonzales et al. 2021; for reviews, see Ito and Cotsarelis 2008; Gonzales and Fuchs 2017; Belokhvostova et al. 2018; Dekoninck and Blanpain 2019). Giving a concrete example, Lgr5- and Lgr6-progenies originating from exclusively distinct stem cell compartments within the HF and IFE both contribute to the leading edge, although with sequential arrival times and Lgr6-progeny being first (Fig. 2C). In the long term, progeny of both IFE and HF stem cell populations can remain in the healed wound epidermis (Ito et al. 2005; Brownell et al. 2011; Page et al. 2013; Vagnozzi et al. 2015; Donati et al. 2017; Joost et al. 2018; Gonzales et al. 2021; Huang et al. 2021).

However, the cellular contribution from different microanatomic locations/stem cell compartments is affected by the type of injury and size of wounds (Fig. 2D). For example, in a sub-epidermal blister model of neonatal skin, cells from the IFE rarely contribute to reepithelialization; instead, HF progeny from the IFE-adjacent junctional zone are a major contributor (Fujimura et al. 2021). Similarly, HF cells are the primary source (>90%) for reepithelialization in shallow (denuded epidermis) and intermediate wounds (HF bulges remain) (Gonzales et al. 2021). Conversely, IFE cells are likely the major source for superficial epidermal damage repair, as removal of the stratum corneum is repaired by local IFE stem cell activation and differentiation (Mesa et al. 2018) and superficial epidermal damage does not induce the emigration of HF bulge cells to the IFE (Kasper et al. 2011). Only upon more severe damage such as full-thickness wounds with simultaneous dermal damage, cells of both IFE and HF compartments contribute to reepithelialization (Ito et al. 2005; Kasper et al. 2011; Page et al. 2013). These observations suggest that damage to the dermis—and associated signals—may be required to induce emigration of HF keratinocytes to the IFE. However, the key signals triggering this cell-fate switch are unresolved.

A series of studies has indicated that an injury-associated microenvironment has the capacity to trigger the dedifferentiation of postmitotic cells in several organs such as the pancreas, liver, intestine, lung, and stomach (for review, see Blanpain and Fuchs 2014). In the skin, it has been recently proposed that a full-thickness wound can enable reprogramming of differentiated cells to a stem cell–like state. Upon wounding, progeny of differentiated Gata6+ cells (sebaceous gland duct) as well as Blimp1+ cells (IFE, HF, sebaceous gland) gained the ability to self-renew in the reepithelialized wound epidermis (Donati et al. 2017).

Given that the presence of HFs or sweat glands is not required for a wound to heal (Ito and Cotsarelis 2008; Langton et al. 2008), and HF damage can repair locally without IFE-cell contribution (Rompolas et al. 2013), a central question remains: “What is the reason, or benefit, of this enormous cellular plasticity for epithelial tissue repair?” A likely answer to this question is that tissues make a constant effort to maintain and restore homeostasis such as through adaptation of nearby cells. The combined knowledge so far suggests that skin wounds increase their healing speed and quality by recruiting cells from all possible epithelial compartments like the HF, IFE, sebaceous gland, or sweat gland.

MOLECULAR DECONSTRUCTION OF THE EPIDERMAL WOUND HEALING PROCESS

Dissecting the wound healing process at a transcriptional level is highly challenging. Every (epithelial) cell's transcriptome within the wound environment is the sum of all influences that a cell experiences at any given moment: the active wound signature (early → mid → late), the original and/or new niche environment (HF → IFE), and its own behavioral status (quiescence → proliferation → migration) (Fig. 3A,B). Major efforts have been made to transcriptionally profile and compare healthy versus wound states using (1) whole tissues, (2) FACS-sorted (selectively enriched) bulk cells, (3) FACS-sorted single cells, and (4) unbiased (non-enriched) single cells. The combined knowledge of these studies provides rich characterization and knowledge of the wound healing process at a molecular level, and we present some highlights in the following paragraphs.

Figure 3.

Figure 3.

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Molecular deconstruction of the epidermal wound healing process. (A) Cellular behavior and metabolic changes based on molecular signatures and functional enrichment. The wound cells’ transcriptome during an active reepithelialization process is a spatially coordinated program of proliferation, migration, and metabolism (Aragona et al. 2017; Haensel et al. 2020). (B) Illustration of how a cell's identity is shaped. Every wound (epithelial) cell's transcriptome is the sum of all influences that a cell experiences at any given moment: the active wound signature (early → mid → late) and the original and/or new niche (hair follicle [HF] → interfollicular epidermis [IFE]) (Joost et al. 2018). (C) Schematic showing transient lineage infidelity and transcriptional convergence of IFE and adjacent HF (including damaged HF) cells during wound reepithelialization revealed by recent scRNA-seq and ATAC-seq (Ge et al. 2017; Joost et al. 2018; Gonzales et al. 2021). (D) Transcriptional adaptation of individual cells revealed through combined lineage tracing and RNA sequencing. Lgr5-traced HF stem cell progeny (Lgr5TOM) gradually lose their typical bulge identity and acquire wound IFE-like identity during reepithelialization. (Panel D is modified from Joost et al. 2018 under the terms of Creative Commons BY-NC-ND 4.0 license.) (E–F) Wound-induced common chromatin accessibility of HF and IFE-derived cells. Dual expression of both lineage transcription factors (TFs) (e.g., IFE-TF KLF5 and HF-TF SOX9) is transiently present in the mobilized cells from both HF and IFE niches (Ge et al. 2017; Adam et al. 2020). Superenhancer: group of enhancers densely occupied by TFs and mediators. Epicenter: enhancer elements where (lineage-specific) TF clustering occurs.

Molecular Signatures Related to Wound Healing

The majority of the now well-known wound-related marker genes have already been described decades ago, by investigating for example mouse and human tissue (mRNA and protein staining), transgenic and knockout mice, RT-PCR/qPCR, or microarrays (Paladini et al. 1996; Johnson et al. 1999; Grose et al. 2002; Pedersen et al. 2003; Cooper et al. 2004; for reviews, see Grose and Werner 2004; Eming et al. 2014). In recent years, this knowledge was further refined through the advancement of single-cell technologies (Joost et al. 2018; Haensel et al. 2020). The most prominent expression differences in the IFE include the well-known wound keratins and integrins (e.g., Krt6a, Krt16, Krt17, Itga5, Itgb1), migratory factors (e.g., Mmp9, Tpm2, Arpc1b, and Cfl1), metabolic enzymes (e.g., Pkm, Ldha, and Ndufa4), inflammation-associated genes (e.g., Cxcl2, Ccl2, Ccl7, Plaur, Procr), and epithelial-to-mesenchymal transition (EMT)-related genes (e.g., Snai2, Vim). Note that these genes are listed to highlight general processes and are far from being complete (for reviews, see Eming et al. 2014; Haensel and Dai 2018). Interestingly, recent scRNA-seq analysis revealed only a mild difference in the global molecular makeup of epithelial cell states between unwounded and wounded skin (Haensel et al. 2020), which may be unexpected at a first glance as tissue injury instantaneously triggers an enormous cascade of signaling events—strong enough to reprogram differentiated cells. However, this finding again fits with the idea of cell functions being determined by the sum of temporospatial gradients, enabling rapid adaptation and cellular flexibility to ensure tissue survival and restoration.

Migratory Leading Edge versus Proliferative Zone

Consistent with the previously observed cellular behavior where the wound-surrounding epithelial tissue was spatially patterned into a migratory wound front, a proliferative zone, and an interplay region (Aragona et al. 2017; Park et al. 2017), recent single-cell transcriptome profiling of the active reepithelialization process in mouse skin revealed spatially coordinated programs of proliferation, migration, and metabolism (Fig. 3A; Haensel et al. 2020).

Cells dominating the migratory leading edge are mostly in a growth-arrest state and display few markers of stemness, while being enriched for genes associated with epidermal differentiation and cell migration including several metalloproteinases (MMPs) (e.g., high levels of Mmp9, Mmp13, and Mmp1b and low levels of MMP inhibitor Timp2), cell adhesion molecules (e.g., protocadherins, integrins, desmosomes, and gap junction proteins), and cytoskeletal proteins (e.g., actin regulators, myosin, and tubulins) (Aragona et al. 2017; Haensel et al. 2020). In contrast, cells dominating the proliferative zone showed early wound response genes (e.g., Fos) as well as genes related to quiescence and stemness (e.g., Trp63, Col17a1) (Haensel et al. 2020). In addition, coupled with the cellular activities, the intrinsic energy metabolisms are also different. Compared to wound proliferative zone cells and cells in unwounded skin, cells of the migratory leading edge (being naturally close to the hypoxic wound bed and the infiltrating immune cells) display low oxidative phosphorylation and higher glycolysis (Fig. 3A; Haensel et al. 2020; Konieczny et al. 2022).

A Plethora of Cell States at Each Wound Repair Time Point

To deconstruct the molecular journey that wound healing epithelial cells experience, for example, if certain wound-related programs exist simultaneously or sequentially, single-cell transcriptome analysis was instrumental. A study by Joost et al. revealed that, even though all wound cells pass through a functionally similar wound healing program over the healing period, each wound-collecting time point (1, 4, 7, 10 days, and >1 month post-wounding) comprises cells that belong to several distinct wound healing cell states. One cell state is present over the entire healing time (permanent wound signature), and others are either transiently present in early wound cells or peaking at intermediate and late wound stages exhibiting a more basal IFE-like expression pattern (Joost et al. 2018). This finding again reflects that each individual cell's identity is determined by its “position” in time and space (i.e., the wound healing progress and location in the tissue) (Fig. 3B).

Cells from Distinct Niches Transcriptionally Converge during Wound Closure

Transcriptional profiling of stem cell progeny from mutually exclusive epidermal niches revealed that cells recruited for reepithelialization, irrespective of their origin, transcriptionally converge over the course of wound healing (Fig. 3C; Joost et al. 2018). For example, Lgr5+ stem cells have an “HF bulge” signature and Lgr6+ stem cells have a “basal IFE” signature before wounding. Upon wounding, both stem cell progenies activate shared transcriptional programs associated with the wound repair process, and bulge cells additionally undergo a gradual change from their original HF identity (e.g., Lgr5, Cd34, Cxcl14, Sparc) to an IFE-like identity (e.g., Krt14, Ifitm3, Eef1b2, Ly6e) (Fig. 3D; Joost et al. 2018). In long-term wound epidermis, these bulge-originating cells become transcriptionally indistinguishable from native unwounded IFE cells (Gonzales et al. 2021).

Transient Lineage Infidelity—A Byproduct or Functionally Relevant for Wound Repair?

Lineage plasticity is critical for wound repair as it allows redirection of the original cell fate to a more favorable one for restoring the skin barrier. Interestingly, during this process keratinocytes in the vicinity of the wound enter a state of lineage infidelity, which is characterized by expression of markers from both the IFE and HF lineage in the same cell (Fig. 3C,E; Ge et al. 2017; Joost et al. 2018). In accordance, profiling of IFE- and HF-derived cells with ATAC-seq (assay for transposase-accessible chromatin using sequencing) showed that both keratinocyte lineages display common chromatin accessibility while reepithelializing the damaged tissue (Fig. 3E,F; Ge et al. 2017; Adam et al. 2020). HF cells juxtaposed to the inflicted wound start to express, in addition to HF genes, transcription factors (TFs) of the IFE lineage (e.g., KLF5, AP2γ). Moreover, the down-regulation of the nuclear factor I (NFI) family TFs appears critical for the HF to IFE cell conversion as NFI TFs play a key role in maintaining HF stem cell identity (Adam et al. 2020). Similarly, mobilized IFE stem cells induce HF-associated TFs (e.g., SOX9, TCF3) before resolving back to IFE. Once both progenies have reached the migratory leading edge, KLF5 (IFE TF) ensures silencing of Sox9 expression (HF TF) to complete the fate switch and restore the wound epidermis permanently (Fig. 3E; Ge et al. 2017). Transient lineage infidelity is mediated by stress-induced TFs such as ETS2 irrespective of stem cell origin, and it is functionally relevant; without the simultaneous expression of key TFs from both lineages, cells fail to integrate in de novo wound epidermis (Ge et al. 2017; Adam et al. 2020).

Cells Remember Their Wound Experience and Lineage Origin

Does “foreign” stem cell progeny (HF → IFE) remember where they came from? Until recently, this remained an intriguing question even though numerous studies have shown that HF progeny in wound epidermis become transcriptionally and functionally equivalent to native IFE cells (Ito et al. 2005; Brownell et al. 2011; Kasper et al. 2011; Page et al. 2013; Vagnozzi et al. 2015; Ge et al. 2017; Joost et al. 2018; Adam et al. 2020; Gonzales et al. 2021). Answering this question, Gonzales et al. probed for chromatin landscape differences of native and wound epidermis cells that originated from HFs and IFE, respectively (Gonzales et al. 2021). Indeed, deconstructing wound-adaptive chromatin states unveiled distinct epigenetic memories depending on a cell's origin: a common wound memory and a niche-specific memory. Compared to native epidermal cells, the wound memory endows wound-experienced cells with enhanced repair ability (secondary wounds heal significantly faster), whereas an HF niche memory enables efficient reversion back to HF stem cells (displaying a highly increased HF reconstitution ability). How does this memory work? Memory of HF-origin chromatin domains, for example, are associated with genes like Sox9, Nfib, and Tcf7l1. These domains can get reactivated upon secondary exposure to an HF (bulge)-niche environment because they remain in a poised open state while adapting to a new environment (Gonzales et al. 2021). This study again highlights the enormous plasticity of skin epithelial cells and reveals that the experience of individual cells can be stored in epigenetic memory, showcasing how nature optimizes tissue regeneration based on cell-collective memories.

WHEN AND WHERE DOES STEM CELL ADAPTATION BEGIN?

By now we know that reepithelialization is a collective effort of cells from all epithelial niches. Furthermore, HF stem cells perfectly adapt transcriptionally and functionally to pursue their new task of restoring and maintaining the wound epidermis, while keeping an epigenetic memory of their past. But when and where does HF stem cell adaption toward an IFE fate start?

Compared to wound-adjacent IFE cells, HF-derived progeny arrive with a short delay of 2 to 3 days post-wounding (dpw) (Vagnozzi et al. 2015; Joost et al. 2018). This delay is not surprising as cells need to relocate from their original HF niche to the IFE, which requires rewiring of their gene expression and protein production toward wound repair and IFE function. Indeed, within 3 dpw, ATAC-seq of HF-derived wound epidermal cells revealed a dramatic loss of bulge chromatin peaks (Gonzales et al. 2021). Probing even earlier at the mRNA level in single cells, HF cells start their adaptation within 24 h after wounding, even before they have left the bulge (Fig. 4A–C; Joost et al. 2018). These 1-day wound-affected bulge cells start to express, in addition to bulge-niche genes, typical early wound-response genes (e.g., Krt6a, Anxa2) as well as receptors (e.g., Cd44, Itgb1, Itga3) for ligands that are provided by the wound environment (e.g., Thbs1, Vcan, Tnc, Spp1) (Fig. 4B–D; Joost et al. 2018). This instant up-regulation of receptors within the bulge niche may be part of the “initial priming” making HF cells receptive for migration, as a number of those receptors are associated with cell migration. Intriguingly, using an unsupervised classification approach, some of the 1-dpw HF cells were already classified as IFE instead of bulge cells, suggesting rapid transcriptome changes at a global level very early in wound healing. This dramatic change of cell identity is mainly reflecting the rapid down-regulation of bulge genes and only partly caused by up-regulation of IFE genes (Joost et al. 2018; Gonzales et al. 2021), which supports the notion that IFE cell identity likely represents the keratinocytes’ default state and HF identity is gained by adding on HF-specific gene-expression modules (Joost et al. 2016). The rapid down-regulation of bulge genes is underpinned by new lineage tracing of Lgr5-expressing bulge cells in relation to wounding time (Fig. 4E). When tamoxifen-mediated labeling was induced after or at the time of wounding, the contribution of Lgr5-traced bulge cells was notably decreased in reepithelialized wounds compared to mice given tamoxifen 1 or 7 days before wounding (Fig. 4E). This further supports a rapid decline of bulge-gene transcription (e.g., Lgr5) within the first 24 h.

Figure 4.

Figure 4.

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Early adaptations of hair follicle (HF) stem cells and their cross talk with the wound environment. (A) Adaptation of bulge cells starts within 1 day post-wounding (dpw). Distribution of Lgr5-traced cells (shown as violin plots) along the bulge → interfollicular epidermis (IFE) pseudotime (see Fig. 3D). Note that 1-dpw cells already span the entire spectrum of bulge → IFE transcriptional identity. (B) Illustration of the signaling cross talk between HF stem cells and the early wound environment. Arrow indicates that the signals secreted from the wound stroma are interacting with up-regulated receptors in the stem cell niche. (C) Detection of Itgb1 and Thbs1 by mRNA fluorescence in situ hybridization (RNA-FISH) in wound sections at 1 dpw. Dashed lines: approximate location of the basement membrane (thin) and wound front (thick). Filled lines: approximate location of the skin surface. (WF) Wound front, (WGA) wheat germ agglutinin (stains cell membranes). Scale bars, 100 μm (panoramas), 50 μm (zoom-ins). (D) Expression of selected receptors in Lgr5- and Lgr6-traced control (unwounded) and early wound cells (which has been defined as wound state 1B in Joost et al. 2018) matching their wound-derived ligand of 1-dpw samples. (Panels A–D reprinted from Joost et al. 2018 under the terms of Creative Commons BY-NC-ND 4.0 license.) (E) Whole-mount top view of lineage-traced wounds from Lgr5creERT2;R26Tomato mice. Adult mice were treated with tamoxifen at indicated times relative to wounding (experimental scheme). Wounds were collected after 12 d and examined for labeling on the wound epidermal side (n ≥ 2 mice per time point) (X. Sun, original data). Dashed lines: outline approximate wound areas. Scale bars, 500 μm.

Strikingly, Lgr6+ basal IFE cells seem already primed for interactions with a wound environment in homeostatic skin. These cells express elevated mRNA levels of wound-interactive receptors already in their steady state, comparably high as wound-adapted bulge progeny (Fig. 4D; Joost et al. 2018). Recent work using intravital imaging demonstrated that Lgr6+ IFE cells are indeed primed for a quick wound response and display more robust growth in the early stages of wound reepithelialization compared to their Lgr6-negative neighbors (Huang et al. 2021). Lgr6+ cells account for ∼20% of basal IFE keratinocytes with no apparent behavioral differences in homeostasis (Füllgrabe et al. 2015; Huang et al. 2021). However, their unique exposure to a microenvironment in close interaction with cutaneous nerves endows them with this increased wound repair promotive ability (Huang et al. 2021).

CONCLUDING REMARKS

The sum of many individual factors shapes a tissue's collective regenerative capacity: local niche signals, epigenetic memory of every cell's experience, and the ability of transcriptional and functional adaptation—called plasticity. Cellular plasticity is a critical feature for an effective repair of epithelial tissue damage, as it allows a redirection of cell fates to more favorable lineages that aid a fast reestablishment of the barrier function.

However, lineage plasticity also brings challenges, such as cell-fate change coupled with new tissue integration of cells carrying mutations can promote tumor initiation, progression, or even cause tumor relapse (Kasper et al. 2011; Page et al. 2013; Ge et al. 2017; Adam et al. 2020; for review, see Lichtenberger and Kasper 2021). Thus, further studies on the controlled promotion (or prevention) of cellular plasticity are particularly appealing to learn how to counteract unfavorable tissue outcomes, such as cancer.

Last, this review is mainly built on knowledge generated from mouse work. To advance wound healing in human skin, mouse-to-human differences must be carefully considered, like species-specific stem cell niche differences or variability of the wound healing process itself (for review, see Zomer and Trentin 2018). Thus, comparative single-cell-omics data analysis between mouse and human skin holds high promise to advance our knowledge for improved applications in regenerative medicine.

ACKNOWLEDGMENTS

We thank the Kasper laboratory members for inspiring discussion and feedback. We also thank Vetenskapsrådet (VR2018-02963), Cancerfonden (21 1821 Pj), LEO Foundation (LF-OC-19-000225), EU H2020-MSCA-ITN-2019 (Cancerprev, 859860), and Karolinska Institutet (2-2111/2019; StratRegen) for their grant support (to M.K.). X.S. and M.K. conceptualized the work (text content, figure content). X.S. and S.J. prepared the figures with input from M.K. X.S. and M.K. wrote the manuscript, with input from S.J.

Footnotes

Editors: Xing Dai, Sabine Werner, Cheng-Ming Chuong, and Maksim Plikus

Additional Perspectives on Wound Healing: From Bench to Bedside available at www.cshperspectives.org

COMPETING INTEREST STATEMENT

The authors have no conflicts of interest to declare.

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