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Hair follicle stem cells as a skin‐organizing signaling center during adult homeostasis

2021; Springer Nature; Volume: 40; Issue: 11 Linguagem: Inglês

10.15252/embj.2020107135

1460-2075

Kefei Nina Li, Tudorita Tumbar,

Skin and Cellular Biology Research

Review20 April 2021free access Hair follicle stem cells as a skin-organizing signaling center during adult homeostasis Kefei Nina Li Kefei Nina Li Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA Search for more papers by this author Tudorita Tumbar Corresponding Author Tudorita Tumbar [email protected] orcid.org/0000-0002-2273-1889 Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA Search for more papers by this author Kefei Nina Li Kefei Nina Li Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA Search for more papers by this author Tudorita Tumbar Corresponding Author Tudorita Tumbar [email protected] orcid.org/0000-0002-2273-1889 Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA Search for more papers by this author Author Information Kefei Nina Li1 and Tudorita Tumbar *,1 1Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA *Corresponding author. Tel: +1 607 3191597; E-mail: [email protected] The EMBO Journal (2021)40:e107135https://doi.org/10.15252/embj.2020107135 PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Stem cells are the essential source of building blocks for tissue homeostasis and regeneration. Their behavior is dictated by both cell-intrinsic cues and extrinsic cues from the microenvironment, known as the stem cell niche. Interestingly, recent work began to demonstrate that hair follicle stem cells (HFSCs) are not only passive recipients of signals from the surroundings, but also actively send out signals to modulate the organization and function of their own niches. Here, we discuss recent findings, and briefly refer to the old, on the interaction of HFSCs and their niches with the emphasis on the outwards signals from HFSCs toward their niches. We also highlight recent technology advancements that further promote our understanding of HFSC niches. Taken together, the HFSCs emerge as a skin-organizing center rich in signaling output for niche remodeling during various stages of adult skin homeostasis. The intricate crosstalk between HFSCs and their niches adds important insight to skin biology that will inform clinical and bioengineering fields aiming to build complete and functional 3D organotypic cultures for skin replacement therapies. Introduction Tissue stem cells are the foundation for adult tissue regeneration, and their cellular states during homeostasis are tightly regulated by (i) cell-intrinsic mechanisms, such as chromatin structure, transcriptional control, and metabolism (Lee et al, 2021) and (ii) cell-extrinsic mechanisms, which encompass the bi-directional molecular crosstalking between stem cells and their functional niche cells. For the study of SC-niche interactions, the mouse hair follicle stem cells (HFSCs) stand out as an excellent model system. The HFSCs periodically undergo activation and quiescence in a highly synchronized manner during the homeostatic hair follicle regeneration (Müller-Röver et al, 2001; Alonso & Fuchs, 2006), and the location and molecular markers of HFSCs are well-defined (Morris et al, 2004; Tumbar et al, 2004). Even more interesting, the whole skin and various cellular compartments within the dermis undergo dramatic remodeling along with the cycling hair follicles (Goldstein & Horsley, 2012; Hsu et al, 2014; Chen et al, 2020), therefore prompting intense investigation into the potential SC-niche crosstalk. Cell–cell signaling from specific niche cells toward HFSCs has been the classical direction of niche-SC communication for studies in the stem cell field. Several reviews considered this direction of communication in-depth (Goldstein & Horsley, 2012; Hsu et al, 2014; Chen et al, 2020; Fuchs & Blau, 2020), and hence, we will only briefly summarize it here. Instead, here we will focus our attention onto the less understood communication with reverse signaling, from the HFSCs outward toward the niche cells in the skin. There is power in numbers, and the clustering of HFSCs in the bulge turns them into a strong signaling center, with influence far beyond cells in their immediate vicinity. In this process, the HFSCs secrete molecules that strongly pattern the organization and behavior of various adult skin compartments, which in turn act as HFSC-niche components during normal skin homeostasis. The skin compartments modulated by HFSCs comprise a rapidly growing list and include such diverse components as the extracellular matrix, nerves, arrector pili muscle (APM), and more recently the skin vasculature to name a few. The emerging niche-organizing function of HFSCs places these stem cells at the very center of skin organization and homeostasis, thus elevating their relevance in skin biology from their basic and somewhat frivolous role (at least in humans, where hair is not required for survival), that of simply producing a hair shaft. Mouse skin is a well-structured, layered tissue that can be divided into epidermis, dermis, and hypodermis (Figure 1). The hair follicle is a skin appendage that protrudes downwards from the epidermis into the dermis. HFSCs orchestrate a highly choreographed series of dramatic hair follicle morphological modifications during homeostasis, known as the hair cycle. The hair cycle consists of several successive and synchronized phases of telogen (rest), anagen (growth), and catagen (regression; Figure 2). Figure 1. Structure of the skin and components of the HFSC niche Skin is composed of epidermis, dermis, and hypodermis layers. Below the hypodermis layer is the subcutaneous muscle layer. The hair follicle is a downward protrusion from the epidermis. HFSCs reside in the outer layer of the bulge region (dark green), and in telogen, they are quiescent. Melanocyte stem cells (black star) are also in the bulge. The inner bulge layer is a non-HFSC population (light green). Above the bulge is the sebaceous gland (orange). The venous annulus is around the upper bulge (dark purple). Sensory nerves innervate the middle bulge (dark blue). Arrector pili muscle (dark brown) connects the bulge and the epidermis. The lymphatic capillaries (yellow line) are along the side of the hair follicle and connect to the lymphatic collecting (yellow line) vessels that are at the bottom of the hair follicle and parallel to the epidermis. Hair germ (gray) locates below the bulge, housing primed HFSCs. Below the hair germ is the dermal papilla (yellow). Around the dermal papilla is the dermal sheath (teal). The hair follicle is closely associated with blood vessels (red), and at this stage, blood vessels concentrate beneath the hair germ and form a horizontal plexus in telogen, with few dispersed blood vessels in the dermis. Dermal fibroblasts (beige) fill the empty space in the dermis. In the hypodermis are adipose tissue (mature and immature adipocytes, yellow and brown, respectively). Immune cells (light blue) also reside in the skin, with some being more mobile than others. (B) In early anagen, HFSCs are activated. The hair germ proliferates and differentiates to make progenitor or transit-amplifying cells that enclose the DP and make the matrix. Melanocyte stem cells migrate downward from the bulge. The sebaceous gland is expanded. Adipocytes undergo hyperplasia and hypertrophy. The horizontal vasculature plexus in telogen (A) proliferates and becomes more vertical toward the epidermis in anagen (B). The lymphatic capillary increases its caliber and disassociates from the bulge at anagen. The dermal sheath also extends to enclose the bottom of the hair. Download figure Download PowerPoint Figure 2. Hair cycle and vasculature dynamics during the hair cycle In telogen when HFSCs (green) and the primed HFSCs in the hair germ are both quiescent, blood vessels (red) concentrate to form a horizontal plexus under the hair germ (HPuHG). Runx1 (purple) is expressed by the hair germ at this stage and regulates the expression of vasculature-related genes. Lymphatic capillaries (yellow) are associated with bulge. Once the hair germ receives the activation signals to enter anagen, the growth phase, hair germ cells start to proliferate and give rise to progenitor cells. Bulge HFSCs proliferate to replenish the stem cell pool. Runx1 expression is diminished. At the same time, blood vessels proliferate and disperse to become more vertical toward the epidermis. Lymphatic capillaries disassociate from the bulge and dilate more relative to their telogen morphology. At full anagen, bulge HFSCs return to quiescence. The progenitor cells that are generated earlier now terminally differentiate to make different inner hair lineages which include a new hair shaft. Morphologically, the hair follicle now spans the entire dermis. Blood vessels keep proliferating, and lymphatic capillaries re-associate with the bulge and become narrow again. At the transition from anagen to catagen the regression stage, bulge cells migrate out of their niche to produce a new hair germ. Then in catagen, differentiated lineages produced in anagen will undergo apoptosis and die, and the hair germ will survive. Both of them have high Runx1 expression. Blood vessels also undergo apoptosis at this stage and begin to change their angle relative to epidermis to adopt a more horizontal orientation again. After all the differentiated lineages in the hair bulb are gone, only the hair germ and bulge cells remain. Hair follicle goes back to telogen and rest, ready for the next round of the hair cycle. The HPuHG is reassembled below the hair follicle. Download figure Download PowerPoint In the hair follicle, a permanent region called bulge harbors the quiescent HFSCs in the outer most cellular layer. A second population of HFSCs called primed SCs which are derived from the bulge, reside temporarily in the structure underneath the bulge known as the hair germ during telogen (Panteleyev, 2018). In the bulge, besides HFSCs, there are also melanocyte stem cells (McSCs) that give rise to differentiated melanocytes for melanin deposition in the colored hair shaft. Surrounding the HFSCs is a mixed neighborhood, which is also the home for many other types of cells of the dermis (Figure 1). Cutaneous nerves are immediately adjacent to HFSCs as they wrap around the bulge for signal relay (Botchkarev et al, 1997). The arrector pili muscle (APM) connects the posterior side of the hair follicle also at the bulge area with the interfollicular epidermis (IFE; Müller-Röver et al, 2001; Fujiwara et al, 2011). Its contraction results in piloerection which has implications in body temperature control and fight-or-flight responses. On the other side of the hair follicle is the lymphatic capillary that collects tissue fluid and drains into the lymphatic collecting vessels beneath the hair follicle (Gur-Cohen et al, 2019; Peña-Jimenez et al, 2019). Right above the bulge is the sebaceous gland filled with sebocytes that release the sebum into the hair canal spanning the skin surface (Niemann & Horsley, 2012). The hair follicle is closely surrounded by the dermal sheath, a population of specialized fibroblast with a recently uncovered contractile function, important for hair follicle regression (Martino et al, 2021). Below the hair germ, there is a ball of mesenchymal cells that is known as the dermal papilla (DP), with known relevance to HFSC activation at the telogen-to-anagen transition (Morgan, 2014; Chen et al, 2020). Outside of the hair follicle, there are fibroblasts in the dermis, adipose tissue in the hypodermis, and blood vessels interlaced in the whole skin. In addition to these tissue niches, the extracellular matrix between cells represents a scaffold that provides essential structural support for all these niche components. When hair follicles begin to grow at the telogen-to-anagen transition, activating signalings such as Shh and Wnt are elevated whereas the inhibitory BMP signaling is suppressed (Alonso & Fuchs, 2006; Lee & Tumbar, 2012). Then, the primed HFSCs in the hair germ form a new hair bulb by rapidly proliferating to first make the hair matrix, a population of multipotent progenitor or transient amplifying cells that can temporarily self-renew and also differentiate during anagen to make a new hair shaft that grows upward (Figure 1). In the meantime, the bulb grows downward pushing the matrix away from the bulge into the hypodermis, and the hypodermis expands at remarkable extent with newly appearing mature adipocytes and vasculature redistributing all around it (Hansen et al, 1984; Mecklenburg et al, 2000; Yano et al, 2001; Festa et al, 2011; Li et al, 2019). The DP is also pushed downward along with the matrix, while the dermal sheath expands around the hair follicle (Figure 1). In parallel, the quiescent HFSC in the bulge temporarily exits quiescence and divides symmetrically a few times while remaining in the bulge, thus expanding the SC pool. Eventually, the balance from activation signals shifts toward inhibitory signals, and together with contact inhibition, push back the bulge HFSCs into quiescence, where they would soon begin to migrate outside the bulge and into the outer root sheath (or layer) of the regressing hair follicle (Waghmare et al, 2008; Zhang et al, 2009; Zhang et al, 2010; Hsu et al, 2011). As the bulb cells are dying out during catagen, the HFSCs survive, and eventually by the next telogen, they will make a new hair germ and a new bulge around the newly formed hair shaft that has now stopped growing (Lee et al, 2021). The dynamic behavior of HFSCs, their maintenance, activation, self-renewal, migration, and differentiation are tightly linked with the fate of various components of the SC niche (Goldstein & Horsley, 2012; Hsu et al, 2014; Chen et al, 2020; Fuchs & Blau, 2020). The idea that HFSCs actively organize their surrounding niches through signaling originated in our two-decade-old work, when we purified H2B-GFP label-retaining HFSCs and obtained their transcriptional profile (Tumbar et al, 2004). This revealed many upregulated genes encoding secreted molecules that were known to regulate other cell types, many of which were co-incidentally neighbors of HFSCs. This finding then led us to propose a speculative model where HFSCs actually crosstalk to their niches—both receiving signals from the niches and also actively modulating the niches (Fuchs et al, 2004). In addition, since niche organization involves multiple molecules and complex regulation, and HFSCs express a multitude of transcription factors such as Sox9 and Runx1 in accordance with their state, a follow-up hypothesis is that HFSCs may use these transcription factors as “master regulators” for niche organization (Fuchs et al, 2004; Lee et al, 2014). Since we proposed this hypothesis, many pieces have been added to shed light to it, but the whole picture is still far from complete. In this review, we will focus on the outward signals from HFSCs to modulate the niche as we understand them today, while also briefly touching upon the reverse signals to clarify the importance of each specific niche to HFSCs. Vasculature We begin our journey with the vascular niche, where recent exciting evidence suggests a novel role of this niche in HFSC activation and skin homeostasis, opening up new avenues of investigation not only in skin, but also in vasculature and endothelial cell biology. The vascular niche has been previously studied in crosstalks with several tissue stem cells such as hematopoietic stem cells, neural stem cells, and muscle stem cells where it maintains homeostasis of the stem cell pool and tissue integrity (Otsuki & Brand, 2017; Sasine et al, 2017; Verma et al, 2018; Mammoto & Mammoto, 2019). Increasing evidence suggests that stem cells can actively recruit or modulate neighboring endothelial cells to create a functional vascular niche around them for stem cell homeostasis or to enhance wound healing (Chen et al, 2008; Donne et al, 2015; Verma et al, 2018). In the skin, the HFSC-vasculature niche consists of two major types of vessels: blood vessels that provide blood flow with oxygen and nutrients and lymphatic vessels that drain the tissue fluid and support immune surveillance (Skobe & Detmar, 2000; Hampton & Chtanova, 2019). Skin biologists have long known that vasculature organizes itself in a specific arrangement around the hair epithelium (Durward & Rudall, 1958; Ellis & Moretti, 1959). Some vasculature structures stay constant throughout the hair cycle in mice, such as the venule annulus which is a venous ring-like vessel formed during hair morphogenesis to be associated with the K15-positive upper bulge (Xiao et al, 2013) (Figures 1 and 2). On the other hand, skin vasculature as a whole is dynamic and keeps up with the morphological changes in hair follicles and in the hypodermis. During the adult hair cycle, in the anagen growth phase, skin vasculature undergoes angiogenesis and in turn may promote hair shaft growth through fueling O2 and nutrients to the matrix progenitor cells (Mecklenburg et al, 2000; Turksen, 2015). In catagen, the perifollicular vasculature collapses along with the regression of the hair follicle. Interestingly, this change in vasculature is associated with and potentially modulated by a down-regulation of VEGF and upregulation of TSP-1 in the follicular keratinocytes (Yano et al, 2001; Yano et al, 2003; Xiao et al, 2013). However, earlier work failed to examine a possible role of vasculature in HFSC activation at stages prior to anagen and the potential molecular crosstalk through signaling between vasculature and HFSCs remained unknown. In contrast to numerous studies done to understand the vascular niche of other tissue stem cells, relatively little effort has been made to understand the HFSC-vasculature crosstalk, until a recent series of several publication on this subject aimed at filling this gap. First, three independent studies all showed that genetic targeting of HFSCs specifically in the epithelium modulates the skin vascular niche organization (Gur-Cohen et al, 2019; Li et al, 2019; Peña-Jimenez et al, 2019; Figure 2). In one of these studies, we found that as HFSCs are activated, a hypodermal vasculature structure that is normally horizontally oriented and crowds vessels underneath the hair germ disperses and becomes more vertical, pointing into the dermis toward the hair follicles and epidermis, as it may proliferate more (Li et al, 2019). This dramatic reorganization of skin vasculature through the hair cycle has not been previously recognized, as earlier work focused on the minute interactions at point of contact between the vasculature and the lower hair bulb and DP (Ellis & Moretti, 1959; McLeod, 1970; Mecklenburg et al, 2000; Yano et al, 2001). Then, as HF pass through anagen and the hair bulbs degenerate at catagen, we found that the vasculature again becomes horizontal forming a dense vascular structure that we refer to as the horizontal(H) plexus(P) underneath (u) the hair germ (HG) during HFSC quiescence, the HPuHG (Figure 2) (Li et al, 2019). Interestingly, our epithelial knockout of Runx1, a transcription factor important for HFSC activation, which is expressed in the primed HFSC in the HG at late catagen and telogen (Figure 2), led to abnormal HPuHG patterning around the hair follicle, which was characterized by increased CD31+ area under the hair germ (Li et al, 2019). These data revealed an association between dense vasculature near the stem cell activation zone (hair germ) and increased quiescence of HFSCs, accompanied by delayed hair cycle progression (Osorio et al, 2008; Li et al, 2019). Microarray data of purified HFSCs from Runx1 epithelial overexpression mice further support the vascular niche-organizing role of HFSCs. This showed altered expression of many genes encoding secreted molecules as Runx1 target genes, such as Ntn4, Sema3a, Figf, and Edn1, to name a few, known to have angiogenesis and vascular patterning functions (Lee et al, 2014; Li et al, 2019). With the exception of Ntn4 (Gur-Cohen et al, 2019), direct targeting of these vasculature-organizing molecules in the hair follicle is awaiting. We did not distinguish between blood vessels and lymphatics remodeling during hair cycle, but given the localization of the CD31-high vasculature considered in our study and well-documented now location of lymphatics, the HPuHG appears to have largely excluded the skin lymphatics. The lymphatic vasculature was timely characterized by two subsequent studies focusing on the interaction between HFSCs and lymphatic capillaries. Both studies revealed that lymphatic capillaries transiently increase their caliber at HFSC activation (Gur-Cohen et al, 2019; Peña-Jimenez et al, 2019). In addition, the association between the lymphatic capillaries and HFSC changes dynamically in a way that the lymphatic capillaries are in close proximity to HFSCs during quiescence and dissociate during HFSC activation (Figure 2) (Gur-Cohen et al, 2019). Closer examination of the lymphatic capillary morphology further revealed that lymphatic capillaries look more fenestrated at anagen onset, potentially conferring a difference in their drainage capacity (Peña-Jimenez et al, 2019). The two studies also converge on finding a HFSCs’ role in regulating the lymphatic vascular niche. Specifically, Peña-Jimenez et al (2019) showed that HFSC-derived Wnt signaling was essential for lymphatic capillaries patterning and for their association with the bulge. In addition, anagen induced by modulation of macrophages (Castellana et al, 2014) recapitulates the increased caliber of lymphatic capillaries in homeostatic anagen, indicating that the hair cycle is a driver of this lymphatic remodeling (Peña-Jimenez et al, 2019). Conversely, transcriptome analysis by Gur-Cohen et al found that HFSCs act as a switch regulating their lymphatic vascular niche by expressing different factors in accordance with their cellular states. Specifically, quiescent HFSCs secrete Angptl7 to promote the lymphatic-HFSC association, whereas activated HFSCs secrete Ntn4 and Angptl4 to promote dissociation (Gur-Cohen et al, 2019). Intriguingly, Ntn4 and Angptl4 are also target genes downstream of transcription factors Runx1 and Tcf3, respectively (Nguyen et al, 2006; Lee et al, 2014; Li et al, 2019), and Runx1 deletion in the epithelium perturbs the nearby vasculature (Li et al, 2019), as discussed above (Figure 3). In combination with the finding from epithelial Runx1 KO mice, it is possible that transcription factors in the hair epithelium are the “master regulators” for vascular niche organization, thus allowing HFSCs to efficiently induce dramatic changes in global gene expression all at once, without tuning each signaling molecule individually. Figure 3. HFSCs crosstalk with niches Hair follicle stem cells and niches crosstalk with each other using various signaling molecules. Black names represent confirmed niche molecules, and gray names represent putative molecules that need further confirmation. Solid arrows indicate confirmed or putative signaling, and dashed arrows indicate unknown signaling. Download figure Download PowerPoint Why would HFSCs need to arrange the vascular niche in a specific organization? Intriguingly, the exact role the vascular niche plays on HFSC behavior is still debatable, and currently, saving some suggestive preliminary observations, there are no signals proven to flow from endothelial cells toward HFSCs to modulate their behavior. Our Alk1 endothelial knockout mice showed increased area of the CD31+ horizontal plexus under the hair germ (HPuHG; Li et al, 2019). This is associated with a hair cycle delay with HFSC activation defects, which we speculate might be due to increased local concentration of the quiescence factor BMP4 (Li et al, 2019). BMP4 is likely secreted by endothelial cells, as also shown in few other stem cell systems including alveolar stem cells, NSCs, and HSCs (Mathieu et al, 2008; Goldman et al, 2009; Chung et al, 2018). Of note, CD31+ vasculature may inhibit HFSC activation in the hair germ possibly via signaling, but at the same time promote hair follicle growth fueled by transit-amplifying matrix cells (Yano et al, 2001). While endothelial cells are often found to maintain the quiescence of other tissue stem cells such as muscle stem cells and neural stem cells (Azevedo et al, 2017; Verma et al, 2018), the role played by lymphatic endothelial cells is more controversial as the ablation of lymphatic vessels and genetically induced changes in lymphatic vessel showed highly mixed outcomes on HFSC behaviors (Gur-Cohen et al, 2019; Peña-Jimenez et al, 2019; Yoon et al, 2019a). Therefore, an urgent question for the field is to more precisely dissect the functions of each type of vasculature on HFSC activity. While recent discoveries shed new light on the HFSC-vascular niche after a long silence in the field, it is just the beginning and a lot more questions on the HFSC-vasculature niche are waiting for answers. For example, signaling from the vascular niche toward the hair remains entirely obscure and the chemokines HFSCs use to modulate the blood vascular niche are yet to be identified, with follow-up functional studies being required. Furthermore, while age-related functional alteration in the vascular niche has been investigated in HSC and NSC (Apple & Kokovay, 2017; Ya-Hsuan & Simón, 2020), current studies on the HFSC-vascular niche mostly focused on the homeostatic condition. Whether the molecular interaction between HFSCs and the vascular niche has any implication in stress conditions, such as injury, is still unknown. Given the importance of the vascular niche in tissue function, integration of endothelial cells into 3D organoid culture systems also greatly enhanced the outcome, to be a more faithful representation of the tissue (Grebenyuk & Ranga, 2019; Vargas-Valderrama et al, 2020). On the other hand, defective crosstalk between stem cell and endothelial cells has an important role in disease progression. In the hematopoietic system, miscommunication between HSCs and their vascular niche can lead to more severe conditions like skewed lineage production in hematopoiesis and anemia (Perlin et al, 2017). In the skin, it has been suggested that abnormal vasculature alterations such as vascularization, perivasculitis, and dilated lymphatic vessels are related to alopecia (Pratt et al, 2017). In addition, neovascularization is often the hallmark of pathological conditions especially various cancers, in which the cancer stem cells can recruit endothelial cells as well as promote nearby endothelial sprouting (Ahn & Brown, 2008; Lugano et al, 2020). Thus, there is a crucial need to study this interaction in molecular details and understand its regulation. Nerves Nerves and neurons have been found to communicate with several tissue stem cells, such as hematopoietic stem cells (HSCs; Agarwala & Tamplin, 2018), intestinal stem cells (Lundgren et al, 2011; Davis et al, 2018; Puzan et al, 2018), and muscle stem cells (satellite cells; Mousavi & Jasmin, 2006; Tatsumi et al, 2009; Yin et al, 2013). In homeostatic condition and in aging, major research efforts have been in the field of HSCs, where innervation was found critical for blood regeneration and HSC mobilization (Agarwala & Tamplin, 2018). Nerves also contribute to intestinal stem cell proliferation and differentiation, and to the barrier function of the gut (Davis et al, 2018; Puzan et al, 2018). In adult muscle tissue, it is well-established that denervation leads to a decline in satellite cell number in the long term (Yin et al, 2013). The satellite cells are also found to secrete neurotrophic factors such as Sema3A and BDNF to maintain a functional nervous niche (Mousavi & Jasmin, 2006; Tatsumi et al, 2009). The interdependence of stem cells and the nervous system is also alluded by cancer studies, revealing bi-directional mutually enhancing interactions between cancer cells and the surrounding nerves (Jobling et al, 2015). Skin is a highly innervated organ with multiple types of nerve fibers (Glatte et al, 2019). In mice, the skin innervation network can be largely divided into three major nerve bundles based on their anatomical location: the sub-epidermal plexus that is right underneath the epidermis, the deep cutaneous plexus that is in the hypodermis, and the subcutaneous plexus that is below the muscle layer (Botchkarev et al, 1997). Out from the three major nerve plexuses, nerve fibers protrude and innervate skin components such as epidermis, the hair follicle, and the arrector pili muscle (APM; Botchkarev et al, 1997; Glatte et al, 2019). During the hair cycle, the whole skin remodels with the hair follicle, and nerves also exhibit plasticity in this process, as shown by earlier work in the nineties (Botchkarev et al, 1997; Botchkarev et al, 1999). Both the follicular innervation and the density of the surrounding nerves in the skin increase in anagen, and decline in catagen, along with changes in neuronal markers expression (Botchkarev et al, 1997; Botchkarev et al, 1999). Sensory nerves have been identified as a niche that modulates HFSC behaviors in wound healing through hedgehog and putative neuropeptide signalings (Brownell et al, 2011; Martínez-Martínez et al, 2012). Besides sensory nerves, sympathetic nerves that innervate the APM and project to the middle bulge play a role in promoting HFSC activation (Fan et al, 2018; Shwartz et al, 2020). Intriguingly, this nerve niche is supported by the APM, together with HFSCs forming a trilineage homeostatic unit (Shwartz et al, 2020). This exciting new finding provides insight on the crosstalk between different HFSC niches and their collective effort on re