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. Author manuscript; available in PMC: 2024 Sep 1.
Published in final edited form as: J Invest Dermatol. 2023 Sep;143(9):1638–1645. doi: 10.1016/j.jid.2023.04.015

Studying Hair Growth Cycle and Its Effects on Mouse Skin

Wei-Hung Wang 1,*, Raul Ramos 2,3,*, Kang-Yu Tai 4, Yun-Shan Wu 1, Tso-Yu Chang 1, Jia-Yu Yan 5, Maksim V Plikus 2,3,#, Ji Won Oh 6,#, Sung-Jan Lin 1,7,8,#
PMCID: PMC10584012  NIHMSID: NIHMS1937542  PMID: 37612030

Abstract

Researchers should be aware that the hair growth cycle drives prominent molecular, cellular, and morphological changes to the entire skin. Thus, hair growth constitutes a major experimental variable that influences interpretation of dermatological studies. Hair growth in mice is neither asynchronous nor fully synchronized, but rather occurs in waves that dynamically propagate across the skin. In consequence, any given area of mouse skin can contain hair follicles in different stages of the cycle in close physical proximity. Further, hair growth waves in mice are initiated by probabilistic events at different points in time and across stochastic locations. The consequence of such stochasticity is that precise patterns of hair growth waves are different from mouse to mouse, even in littermates of the same gender. Yet, commonly, such physiological stochasticity is misconstrued as a significant hair growth phenotype in mutant mice or in drug-treated animals. The purpose of this article is to provide a set of guidelines for designing reliably interpretable murine studies on hair growth and to inform of key experimental caveats that should be avoided. It also informs on how to account for and minimize the impact of physiological hair cycle differences when designing and interpreting non-hair growth dermatological studies in mice.

Introduction

Because mice are quadrupedal, and their dorsal skin is easily accessible, most dermatological studies are naturally conducted on the animals’ back. One of the defining features of the mouse skin is its numerous pelage hair follicles (HFs). Because HFs cyclically remodel as they grow, it becomes essential to account for hair cycle phase in all skin studies, even if the investigators’ primary research interest does not lie within the area of hair biology.

Hair cycle consists of three consecutive phases of active growth (anagen), regression (catagen), and relative quiescence (telogen) (Muller-Rover et al., 2001). Upon transition from telogen to anagen, the cellular composition and size of HFs change significantly. Telogen HFs are diminutive and fully reside within dermis. Their epithelial compartment primarily consists of progenitor cells in the bulge and hair germ, situated above dermal papilla (DP), its principal signaling niche (Sennett and Rendl, 2012) (Figure 1). During anagen, HFs significantly enlarge and extend downward into dermal white adipose (dWAT) layer. Their epithelial progenitors rapidly proliferate, giving rise to the entire lower portion of the follicle, including outer root sheath (ORS), companion layer, inner root sheath (IRS), hair shaft and hair matrix (Figure 1). Proliferation by matrix cells sustains continuous hair growth, a process principally regulated by signals from the DP, which has now migrated downward (Sennett and Rendl, 2012). After a period of growth which lasts for approximately two weeks, HFs undergo catagen, a regression process during which much of their lower epithelium involutes (Mesa et al., 2015). Catagen HFs “shrink” upward, eventually assuming the telogen morphology and concluding a full cycle. A fully grown hair fiber (aka club hair) stays retained within the telogen HF bulge. In mice, dorsal HFs can retain up to four club hairs from consecutive cycles, before shedding them (Lay et al., 2016). This way, dorsal pelage achieves a hair density that significantly exceeds that of actual HFs.

Figure 1: Schematic representation of the hair growth cycle.

Figure 1:

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(a) Following embryonic morphogenesis (left) HFs directly progress into first (aka developmental) hair growth cycle (right). Three principal phases of the hair growth cycle (anagen, catagen and telogen), associated changes in the HF morphology and key HF cell types and compartments are color-coded and annotated. (b) Schematic depiction of the hair growth wave, wherein neighboring HFs in progressively mature phases of the hair growth cycle (from telogen to anagen VI) are laid out in space (from right to left). More detailed HF cell types and compartments are color-coded and annotated on the left.

Importantly, as pelage HFs cycle, numerous extrafollicular skin compartments also remodel. For example, compared to telogen, anagen skin expands its vascular network (Li et al., 2019) and dWAT (Zhang et al., 2016), and undergoes changes in its immune cell repertoire (Castellana et al., 2014). Therefore, cellular composition and expression profiles across virtually all skin compartments prominently differ across hair cycle, and the latter should be regarded as the major variable when designing and interpreting skin studies in mice.

Mouse Hair Grows in Coordinated Waves

Unlike adult humans, whose scalp HFs grow largely asynchronously, or seasonal mammals that molt synchronously, hair growth in laboratory mice is coordinated locally as waves (Plikus and Chuong, 2008) (Figure 1b). When fur is shaved in non-albino mice, a differentially colored skin pattern is revealed, with light pink telogen and pigmented anagen skin patches (Figure 2). In adult mouse skin, melanocyte lineage is restricted to HFs. Telogen HFs contain melanocyte stem cells but not pigment-making melanocytes and, as a result, telogen skin appears unpigmented when closely shaved. On the other hand, anagen HFs contain melanocytes that deposit pigment into growing hair shafts and, thus, shaved anagen skin appears pigmented. Pigmentation is faint during early anagen, but quickly darkens as new hair shafts emerge above the surface. During catagen, melanogenesis shuts down and skin pigmentation disappears. Therefore, periodic changes in skin pigmentation in mice serve as a reliable non-invasive readout for hair cycle stages.

Figure 2: Key aspects of the long-term hair cycle tracking experiment.

Figure 2:

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(a) Fur shaving setup with “pet grade” hair clipper is shown on the left. The panel on the right shows the appropriate method for holding animals during fur shaving to help minimize accidental skin cuts. Arrow indicates shaving direction. (b-d) Representative examples of commonly observable dorsal hair growth patterns in adult shaved mice in late 2nd telogen (b), early 3rd anagen (c), and beyond 4th anagen (d). In (c), green arrowhead points to an anagen initiation center on the upper dorsal skin, while green arrows point to bilaterally symmetric ventral-dorsal hair growth waves. (e-g) Inverted view (dermal side up) of dissected skin from the animal shown in (c). In (e, left), arrowhead points to the initiation center and arrows point to hair growth waves. In (e, right), schematic drawing of the skin from (e, left) is show with regions in anagen (green), catagen (yellow) and telogen (red) color-coded. In (f), magnified view of the spontaneous hair growth initiation center is shown. Centrifugal hair growth wave is evident, and its portion is show on insert (f, right). In (g), magnified view of the ventral-dorsal catagen wave and sharp anagen-telogen domain boundary is shown and annotated.

Shaved mice display variable patterns of pigmented skin patches, whose exact number, size, shape and spatial distribution differ across individual animals, even in gender-matched littermates. However, when such pigmented patches are tracked over time in the same animal, recurrent changes emerge (Plikus et al., 2011, Plikus et al., 2008). Typically, each anagen patch starts as a small initiation center, which then “grows” as a wave into the surrounding telogen skin (Figure 2b, 2f). Waves originating from two or more initiation centers can merge, while in other instances wave propagation stops and discrete domains with sharp anagen-telogen boundaries form (Figure 2b, 2g).

Molecular Bases of Hair Growth Waves

Hair growth waves are driven by signaling interactions among adjacent HFs and between HFs and surrounding extrafollicular cells. Collectively defined as signaling macro-environment, these sources of signals can prominently modulate timing of anagen entry by individual HFs and drive hair wave formation. Anagen HFs at the wavefront express high levels of WNT ligands that propagate and trigger WNT activation in nearby telogen HFs, where WNT activation serves as a signaling prerequisite for anagen entry. As telogen HFs enter anagen, they also produce WNT ligands that in turn stimulate anagen entry in surrounding telogen HFs. As such, anagen induction propagates as a self-sustaining chain reaction (Plikus et al., 2011). Importantly, in certain instances wave propagation abruptly stops, and sharp anagen-telogen boundaries form. This occurs when the propagating wave encounters HFs that have recently completed their cycle. Indeed, HFs that have recently entered telogen are generally resistant to high WNT signals for approximately one month and regain responsiveness afterwards. On these bases, telogen is divided into early refractory and late competent phases. The refractory behavior of early telogen HFs is caused by high BMP signaling in their stem cell niches, sustained by BMP ligands produced in dWAT (Plikus et al., 2008).

Age-Dependent Hair Growth Changes

Developmental anagen follows hair morphogenesis, becoming apparent at around postnatal day 4 (P4). Mouse skin contains HFs from three successive waves of morphogenesis (Tsai et al., 2014), that occur asynchronously across the dorsum, resulting in more mature HFs in the shoulder region of newborn mouse skin compared to lumbar skin (Wang et al., 2017). Developmental telogen is short and lacks a refractory period. The first postnatal anagen occurs as a rostro-caudal wave and shows bilateral symmetry. The latter is consequence feature of anagen starting in ventral skin first, from where it propagates onto the dorsum over both shoulders (Wang et al., 2017). First postnatal telogen becomes significantly longer and displays molecular signatures of refractivity (Greco et al., 2009). Second anagen commonly retains rostro-caudal wave and features of bilateral symmetry. However, bilateral symmetry disappears during third and following cycles. Instead, hair growth patterns become asymmetric and driven by stochastic initiating events in the dorsum, rather than by ventral-dorsal waves. Another key feature that emerges in the third cycle is formation of hair growth domains with discrete boundaries at sites where anagen waves “collide” with refractory telogen skin (Plikus and Chuong, 2008) . Such domains are usually large in young mice, with each occupying half or more of the dorsum. Yet, with each consecutive cycle, the iterative processes of wave propagation and boundary formation fragments dorsal skin into ever smaller domains (Figure 2d). Mice over 18 months old display particularly small, asymmetric hair growth domains (Chen et al., 2014).

Common Mistakes in Hair Growth Studies

Below we discuss common experimental mistakes caused by lack of consideration for the wave mechanism of hair growth. First, significant differences in hair growth between mutant and control mice may be wrongly inferred if based only on histological differences in a small skin region. Such histological differences can be reflective of natural hair growth stochasticity and need to be complemented by hair cycle tracking in shaved mice. Second, hair growth-activating properties of systemically or topically applied candidate drugs are often claimed based on observing multiple and/or large hair growth patches. However, potent drugs should override the wave mechanism and induce broad hair regrowth over the entire treated skin. For more precise testing, hair growth induction should be assayed with topical spot applications or intradermal microinjections, with a vehicle control on the same animal in an adjacent area. Third, changes in cellular composition between mutant vs. control skin are concluded in assays that require tissue dissociation, such as flow cytometry or single-cell RNA-sequencing. However, natural variations in hair cycle between samples can produce cell abundance differences across HF and extrafollicular lineages. Hair cycle stages for all skin samples used for cell isolation should be confirmed on wholemount examination and/or express cryosection histology.

How to Design Hair Cycle Experiments

Long-term hair growth tracking.

We recommend studying hair growth in mice by periodically shaving and photographing them, followed by image analysis (Figure 2). Electric hair clippers should be used to carefully shave fur off the entire dorsum in anaesthetized animals. Shaving should be done in a posterior-to-anterior direction, with care taken to not wound the skin (Figure 2a). Shaved skin can be wiped with a moist towel to remove excess hair and mice should then be photographed on a high-contrast background with a ruler for scale. Despite its simplicity, researchers should be aware of important points. First, skin cuts will initiate a wound healing response, which can induce precocious hair growth. To reduce risk of accidental wounding, we recommend shaving with small, “pet grade” hair clippers, holding mice to create a taut skin surface. Animals with cuts should be removed from the study. Second, depilatory creams should be avoided, as they disrupt the epidermal barrier and result in local inflammation, risking precocious anagen induction. And third, crowded mouse cages result in fights and skin scratches, which in turn trigger premature anagen. For long term hair cycle monitoring, mice should be housed individually.

We recommend a minimum of 10 replicate animals to account for inevitable losses from accidental skin cuts. Cages should be supplied with extra nesting material to provide warmth. We recommend tracking mice from the middle of first anagen, starting from P35 and to periodically shave fur and retake pictures every other day. We recommend tracking mice for long enough to record at least three consecutive full hair cycles, at least in some body sites. The exact duration of each study can vary, but it is typically on the order of 6 months. At the end, photographs should be chronologically arranged and analyzed to determine: (i) anagen and telogen duration in each hair growth domain; (ii) frequency of spontaneous initiation centers; (iii) speed of anagen wave propagation; (iv) size of individual domains. The above parameters can then be compared between mouse groups using appropriate statistical approaches.

Short-term experiments on early hair cycles.

Developmental telogen is short, lasting between P18 and P24, and a delay of a 2–3 days in the onset of first anagen is significant. In mutant mice, such a delay can be interpreted as the outcome of increased HF stem cell quiescence or reduced anagen-promoting signaling molecules. First telogen lasts longer than developmental telogen and shows prominent gender differences: in females it lasts between P42–72 (Greco et al., 2009), while in males only between P42–53 (Wang et al., 2017). Thus, only mice of the same gender should be compared. For example, in females P42–56 are considered functionally refractory telogen days, while those after P56 as functionally competent. If mutant female mice display new anagen before P56, this suggests loss of HF stem cell quiescence or an increase in anagen activators. For more precision, second anagen status should be compared at the same anterior-posterior level (i.e., shoulder skin should be compared only to shoulder skin). Comparing between regions (e.g., shoulder skin in one mouse to lumbar skin in another) can lead to critical misinterpretations.

Histology of hair growth waves.

HFs and surrounding skin structures change their morphology, cellular composition, and gene expression across the hair cycle. Studying such changes is typically achieved by examining numerous skin samples from multiple mice, each representing one hair cycle stage. An alternative approach takes advantage of the fact that a propagating hair growth wave contains HFs in all consecutive stages of the cycle spatially distributed in a linear order (Figure 2f, 2g). As such, all hair cycle stages can be represented within a single skin area 1 cm or less in size (Plikus and Chuong, 2008, Plikus et al., 2008), which can be processed for histology in a way that preserves it’s naturally flat state (Figure 3). Molecular detection assays (e.g., in situ hybridization or immunostaining) done on such skin samples can uncover hair cycle-dependent molecular expression dynamics with extraordinary temporal resolution.

Figure 3. Step-by-step guide to preparing mouse skin for histological analysis.

Figure 3.

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Numbered and annotated images illustrate key technical aspects of skin preparation: spreading (steps 1, 2), trimming (steps 3, 4), and embedding for paraffin-based histology (steps 5–8).

Quantitative hair plucking.

Unlike indiscriminate depilation, the precise plucking of an exact, small number of hairs is an informative assay into hair cycle properties. Club hair plucking from telogen HFs introduces micro-injury to bulge stem cells, which respond by secreting cytokines (Chen et al., 2015). Further, cells at the base of club hair express anagen antagonists, such as FGF18 (Kimura-Ueki et al., 2012). Therefore, the event of plucking is sensed by HFs as a trigger for new anagen. Importantly, the response of plucked HFs to this trigger is not autonomous, and hair plucking of one or few HFs will not result in their regrowth. Instead, the plucking of 50 adjacent hairs is always followed by new anagen, with its timing dependent on the competence status of the skin (i.e., plucking-induced anagen starts faster during competent vs. refractory telogen (Plikus et al., 2008)). We recommend using quantitative plucking to assay changes in telogen refractivity between mutant and control mice. Prior to plucking, mice should be shaved and physiological telogen onset should be determined (i.e., day when shaved skin becomes non-pigmented). To pluck hairs during refractory telogen, we recommend doing so on day 10 of telogen, and on day 30 for competent telogen. Shaving with clippers leaves approximately 2 to 4 mm of hair fiber, sufficiently long so that they can plucked out using forceps (Figure 4a, 4b). Plucking should be done on fully anaesthetized mice under a stereomicroscope with constant monitoring. After demarcating an area, hairs should be counted as they are being plucked. Care should be taken to not pinch the skin, which causes micro-injury and induces wound repair response. Plucked area location should be apparent but can be additionally marked with non-toxic skin marker. On average, in competent telogen skin, 50 and 200 plucked hairs stimulate HFs to enter anagen and reach anagen V (clearly pigmented HFs) by day 13 and 9, respectively. In refractory skin, these days are 42 after 50 plucked hairs and 28 after 200 plucked hairs (Plikus et al., 2008). Changes in temporal response to quantitative plucking between mutant vs. control mice can serve as functional validation of altered telogen refractivity.

Figure 4. Visual guide to quantitative hair plucking and pelage depilation experiments.

Figure 4.

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(a) Experimental setup for quantitative hair plucking experiments. Using an inoculating loop or any blunt plastic object, stretch the telogen skin to facilitate individual hair plucking with fine forceps. (b) Typical appearance of skin following quantitative plucking of 50 (yellow arrowheads) and 200 (green arrowheads) adjacent hairs. Experiments should be organized contra laterally and mirrored along the anterior-posterior axis when possible. Magnified view of skin following plucking of 50 (c) and 200 (d) adjacent hairs is shown. (e) Wax strip depilation setup. Melt wax strip at temperatures below 55 °C, apply onto the dorsal side of a previously shaved mouse and strip swiftly towards the head. (f) Representative hair growth induction timeline following wax strip depilation. Mice should be carefully periodically shaved during the induced anagen stage to better visualize transition into telogen.

Hair cycle resetting with depilation.

Hair depilation, such as waxing, is commonly used to induce new anagen. It is usually performed to either: (a) “reset” hair cycle and quickly obtain skin samples with uniform anagen HFs; or (ii) test for anagen delay phenotypes in mutant mice. Despite its convenience, this assay has many caveats, and proper consideration should be taken if it is to be performed. The plucking of club hairs, normally lodged within HF bulges, dramatically alters stem cells, inducing their damage and death. Wax depilation can also cause unintended physical or thermal injury, which may in turn trigger complex skin repair responses. Therefore, the mechanism behind depilation-induced hair growth may not reflect the nature of a physiological hair cycle. Moreover, it is challenging to estimate refractory or competent telogen status on unshaven skin. Since “telogen history” prominently impacts timing of anagen initiation, disregarding it in each experimental mouse can result in erroneous interpretations (e.g., a group of mice depilated in refractory telogen show an apparent delay in hair growth and is erroneously attributed to genotype). If performed, we recommend closely shaving the animal beforehand to establish a record its “telogen history” as well as using low melting temperature (<55 °C) wax strips. Wax depilation should be followed by a thorough examination for burns or accidental tissue tears (Figure 4e, 4f).

Topical drug-induced hair growth.

Topical application of small molecules to modulate hair growth is a commonly used assay by hair biologists. Molecules with known properties are used to test if their effect becomes altered in mutant mice, while new compounds are tested for possible hair growth-modulating potential. To be topically bioavailable, molecules need to be delivered using organic solvents, commonly ethanol or DMSO. Molecules that are not soluble in organic compounds, or large molecules would not be appropriate candidates for topical testing. Application should be performed on shaved anaesthetized animals. Drug and vehicle control should be applied onto approximately 10 mm skin spots using a plastic inoculating loop or pipette tip with total volume not exceeding 20 μl per application (Figure 5d). As with quantitative hair plucking, it is essential that drug treatment is performed on telogen skin with a known “telogen history,” and that the drug and vehicle treatment is done on the same animal with application spots at least 20 mm apart to minimize cross-contamination. Depending on the chemical nature of the compound and its known or hypothesized mode of action (i.e., direct effect on HF stem cells vs. indirect effect via immune cell modulation), single dose treatment can be sufficient, or it may need to be repeated. In the latter case, we recommend repeating applications with 24 hour intervals and to limit protocol to three consecutive applications. Because organic solvents and certain drugs can induce skin irritation and itch, mice might actively groom skin at treatment sites. Other mice can also groom experimental animals. Therefore, we recommend separating mice for the duration of the experiment, limiting drug application to the hard-to-groom shoulder region and/or placing a surgical cone. Depending on the mode of action and use of refractory vs. competent skin, potent anagen inducers (such as Sonic Hedgehog agonist (SAG) or cyclosporine A) can show definitive anagen initiation (and, consequently, skin pigmentation) at the treatment sites in as little as 7 days (Plikus et al., 2008). However, for rigorous testing comparing drug vs. vehicle effects should be done on the same animal.

Figure 5. Visual guide to microinjection and topical drug application for hair growth induction.

Figure 5.

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(a) Example of a pneumatic microinjector rig for skin injection. (b) Shaven telogen skin for microinjection; the dashed box encloses the experimental area. (c) Detail from the experimental area in (b), showing individual steps and key information for mouse skin microinjections. (d) Example of a solution being applied topically on a clean shaven mouse with known “telogen history”. Avoid spreading the volume over too large an area and use the contralateral side at the same level for vehicle controls. For purposes of demonstration, a colored solution was used in panels (c) and (d).

Intradermal drug injections.

An assay that measures hair growth-modulating effects of large size water-soluble molecules (e.g., recombinant proteins) is intradermal injection. When performed, investigators should account for the same considerations as in the above described topical treatment experiments. The following are additional technical recommendations. Because mouse skin is relatively thin, it is challenging to consistently inject solution intradermally using clinical-grade injectors like insulin syringes. Moreover, it is challenging to administer volumes of solution of less than 10 μl. As a result, injected solution tends to migrate below dermis, into dWAT, or leak out under the hydrostatic pressure of injection. This limits reproducibility and reliability of injections, whose primary goal is to modulate telogen HFs that in mice reside fully above dWAT. We recommend to micro-inject aqueous drugs using pulled-glass micropipettes coupled to a microinjector rig (Figure 5). Microinjections should be performed on fully anaesthetized animals under constant visual monitoring via stereomicroscope. A capillary glass needle can be reliably driven into upper dermis at a shallow angle, and up to 10 μl of solution can be injected per test site. To test hair growth-inducing effect of recombinant proteins, we recommend injecting the same test site with 3 μl of solution at 24 hour intervals, using solution of Bovine Serum Albumin (BSA) as a negative control, and assaying injected sites for hair growth on day 14 (Liu et al., 2022). Considering the small size of micro-injected sites, care should be taken to reliably mark them for future examination. Repetitively marking site with non-toxic skin marker or implanting several colored agarose micro-beads can reliably mark test sites.

Accounting for Hair Cycle in Non-Hair Cycle Experiments

Because numerous extrafollicular skin cell populations undergo hair cycle-dependent changes in composition and gene expression, it is natural that hair cycle is a major biological variable that can affect the outcome of a multitude of dermatological studies whose primary goal may not be hair biology. The techniques described to precisely match hair cycle stages between experimental animals should be used in studies on: (i) wound healing, (ii) skin tumorigenesis, and (iii) dermal adipose tissue metabolism, among others. Indeed, healing of excisional skin wounds in mice occurs faster when wounds are inflicted in anagen vs. telogen skin (Ansell et al., 2011). Less quiescent epithelial progenitors, dense micro-vascularization, and signature immune cell composition of anagen skin are likely reasons for this phenomenon. Skin susceptibility to chemical- or radiation-induced tumorigenesis is particularly high during early anagen, which correlates with the lowest quiescence status by epithelial HF stem cells that can serve as tumor-initiating cells (Mancuso et al., 2006, Miller et al., 1993). dWAT is significantly thicker in anagen vs. telogen skin, as it undergoes expansion driven by anagen HF signals, such as Sonic Hedgehog (Zhang et al., 2016). This expansion is largely non-metabolic and not associated with adipose tissue hypertrophy in other depots.

Conclusion

We describe how laboratory mice grow their hair via coordinated wave mechanism and its essential spatial and temporal dynamics. We also describe a non-invasive experimental technique to study hair growth waves, and detail how to match hair cycle stages between experimental and control mice in order to achieve reliable results in a number of dermatological studies, both on hair and non-hair skin biology.

Summary points:

  • Periodic photography of shaved mice allows non-invasive study of normal hair growth dynamics based on hair cycle-coupled skin color changes.

  • To reliably evaluate the effect of candidate drugs on hair growth, their application must be timed to either early refractory or late competent telogen phases.

  • Precise hair plucking permits quantifying hair growth responses between mutant and control mice.

Limitations:

  • Non-invasive hair cycle studies are inherently lengthy and require approximately six months to complete.

  • Mice that sustain a skin injury, which triggers premature hair growth, should be removed from hair cycle studies. This necessitates a relatively large initial mouse sample size.

Acknowledgements

SJL is supported by the Taiwan Ministry of Science and Technology (110-2314-B-002-035-MY3), National Taiwan University (110L893001), Taiwan National Health Research Institutes (NHRI-EX110-10811EI). JWO is supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (NRF-2020R1A5A2017323 and NRF-2021R1C1C1014425). MVP is supported by LEO Foundation (LF-AW-RAM-19-400008 and LF-OC-20-000611), Chan Zuckerberg Initiative (AN-0000000062), W.M. Keck Foundation (WMKF-5634988), NSF (DMS1951144), and NIH (U01-AR073159, R01-AR079470, R01-AR079150, R21-AR078939, P30-AR075047). WHW is supported by a postdoctoral fellowship from the Taiwan Ministry of Science and Technology (110-2811-B-002-559).

Footnotes

Conflict of Interest

The authors declare that they have no competing interests.

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