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    A novel and safe small molecule enhances hair follicle regeneration by facilitating metabolic reprogramming. Son Myung Jin,Jeong Jae Kap,Kwon Youjeong,Ryu Jae-Sung,Mun Seon Ju,Kim Hye Jin,Kim Sung-Wuk,Yoo Sanghee,Kook Jiae,Lee Hongbum,Kim Janghwan,Chung Kyung-Sook Experimental & molecular medicine Targeting hair follicle regeneration has been investigated for the treatment of hair loss, and fundamental studies investigating stem cells and their niche have been described. However, knowledge of stem cell metabolism and the specific regulation of bioenergetics during the hair regeneration process is currently insufficient. Here, we report the hair regrowth-promoting effect of a newly synthesized novel small molecule, IM176OUT05 (IM), which activates stem cell metabolism. IM facilitated stemness induction and maintenance during an induced pluripotent stem cell generation process. IM treatment mildly inhibited mitochondrial oxidative phosphorylation and concurrently increased glycolysis, which accelerated stemness induction during the early phase of reprogramming. More importantly, the topical application of IM accelerated hair follicle regeneration by stimulating the progression of the hair follicle cycle to the anagen phase and increased the hair follicle number in mice. Furthermore, the stem cell population with a glycolytic metabotype appeared slightly earlier in the IM-treated mice. Stem cell and niche signaling involved in the hair regeneration process was also activated by the IM treatment during the early phase of hair follicle regeneration. Overall, these results show that the novel small molecule IM promotes tissue regeneration, specifically in hair regrowth, by restructuring the metabolic configuration of stem cells. 10.1038/s12276-018-0185-z
    Cell Types Promoting Goosebumps Form a Niche to Regulate Hair Follicle Stem Cells. Shwartz Yulia,Gonzalez-Celeiro Meryem,Chen Chih-Lung,Pasolli H Amalia,Sheu Shu-Hsien,Fan Sabrina Mai-Yi,Shamsi Farnaz,Assaad Steven,Lin Edrick Tai-Yu,Zhang Bing,Tsai Pai-Chi,He Megan,Tseng Yu-Hua,Lin Sung-Jan,Hsu Ya-Chieh Cell Piloerection (goosebumps) requires concerted actions of the hair follicle, the arrector pili muscle (APM), and the sympathetic nerve, providing a model to study interactions across epithelium, mesenchyme, and nerves. Here, we show that APMs and sympathetic nerves form a dual-component niche to modulate hair follicle stem cell (HFSC) activity. Sympathetic nerves form synapse-like structures with HFSCs and regulate HFSCs through norepinephrine, whereas APMs maintain sympathetic innervation to HFSCs. Without norepinephrine signaling, HFSCs enter deep quiescence by down-regulating the cell cycle and metabolism while up-regulating quiescence regulators Foxp1 and Fgf18. During development, HFSC progeny secretes Sonic Hedgehog (SHH) to direct the formation of this APM-sympathetic nerve niche, which in turn controls hair follicle regeneration in adults. Our results reveal a reciprocal interdependence between a regenerative tissue and its niche at different stages and demonstrate sympathetic nerves can modulate stem cells through synapse-like connections and neurotransmitters to couple tissue production with demands. 10.1016/j.cell.2020.06.031
    Hair follicle aging is driven by transepidermal elimination of stem cells via COL17A1 proteolysis. Matsumura Hiroyuki,Mohri Yasuaki,Binh Nguyen Thanh,Morinaga Hironobu,Fukuda Makoto,Ito Mayumi,Kurata Sotaro,Hoeijmakers Jan,Nishimura Emi K Science (New York, N.Y.) Hair thinning and loss are prominent aging phenotypes but have an unknown mechanism. We show that hair follicle stem cell (HFSC) aging causes the stepwise miniaturization of hair follicles and eventual hair loss in wild-type mice and in humans. In vivo fate analysis of HFSCs revealed that the DNA damage response in HFSCs causes proteolysis of type XVII collagen (COL17A1/BP180), a critical molecule for HFSC maintenance, to trigger HFSC aging, characterized by the loss of stemness signatures and by epidermal commitment. Aged HFSCs are cyclically eliminated from the skin through terminal epidermal differentiation, thereby causing hair follicle miniaturization. The aging process can be recapitulated by Col17a1 deficiency and prevented by the forced maintenance of COL17A1 in HFSCs, demonstrating that COL17A1 in HFSCs orchestrates the stem cell-centric aging program of the epithelial mini-organ. 10.1126/science.aad4395
    Internalization of the TAT-PBX1 fusion protein significantly enhances the proliferation of human hair follicle-derived mesenchymal stem cells and delays their senescence. Wang Bo,Liu Feilin,Liu Zinan,Han Xing,Lian Aobo,Zhang Yuying,Zuo Kuiyang,Wang Yuan,Liu Mingsheng,Zou Fei,Jiang Yixu,Jin Minghua,Liu Xiaomei,Liu Jinyu Biotechnology letters OBJECTIVES:To express a TAT-PBX1 fusion protein using a prokaryotic expression system and to explore potential effects of TAT-PBX1 in the proliferation and senescence of human hair follicle-derived mesenchymal stem cells. RESULTS:The TAT-PBX1 fusion was produced in inclusion bodies and heterogenously expressed in Rosetta (DE3) cells. Immunofluorescence staining showed that TAT-PBX1 fusion proteins were internalized by human hair follicle-derived mesenchymal stem cells. The growth rate of cells was increased after treatment with more than 5.0 μg/mL of TAT-PBX1. The rate of senescence-associated β-galactosidase positive cells was reduced in the 10.0 μg/mL TAT-PBX1 group (28%) than the 0 μg/mL control group (60%). Cells treated with the TAT-PBX1 fusion protein showed higher expression of p-AKT (1.22-fold that of the control), which indicates that TAT-PBX1 activated AKT pathway after cellular uptake. CONCLUSIONS:The TAT-PBX1 fusion protein increased the proliferation of hair follicle mesenchymal stem cells and delayed their senescence by activating the AKT pathway following internalization by cells. 10.1007/s10529-020-02909-x
    SIRT7 activates quiescent hair follicle stem cells to ensure hair growth in mice. Li Guo,Tang Xiaolong,Zhang Shuping,Jin Meiling,Wang Ming,Deng Zhili,Liu Zuojun,Qian Minxian,Shi Wei,Wang Zimei,Xie Hongfu,Li Ji,Liu Baohua The EMBO journal Hair follicle stem cells (HFSCs) are maintained in a quiescent state until activated to grow, but the mechanisms that reactivate the quiescent HFSC reservoir are unclear. Here, we find that loss of Sirt7 in mice impedes hair follicle life-cycle transition from telogen to anagen phase, resulting in delay of hair growth. Conversely, Sirt7 overexpression during telogen phase facilitated HSFC anagen entry and accelerated hair growth. Mechanistically, Sirt7 is upregulated in HFSCs during the telogen-to-anagen transition, and HFSC-specific Sirt7 knockout mice (Sirt7 ;K15-Cre) exhibit a similar hair growth delay. At the molecular level, Sirt7 interacts with and deacetylates the transcriptional regulator Nfatc1 at K612, causing PA28γ-dependent proteasomal degradation to terminate Nfatc1-mediated telogen quiescence and boost anagen entry. Cyclosporin A, a potent calcineurin inhibitor, suppresses nuclear retention of Nfatc1, abrogates hair follicle cycle delay, and promotes hair growth in Sirt7 mice. Furthermore, Sirt7 is downregulated in aged HFSCs, and exogenous Sirt7 overexpression promotes hair growth in aged animals. These data reveal that Sirt7 activates HFSCs by destabilizing Nfatc1 to ensure hair follicle cycle initiation. 10.15252/embj.2019104365
    Epidermal Growth Factor Induces Proliferation of Hair Follicle-Derived Mesenchymal Stem Cells Through Epidermal Growth Factor Receptor-Mediated Activation of ERK and AKT Signaling Pathways Associated with Upregulation of Cyclin D1 and Downregulation of p16. Bai Tingting,Liu Feilin,Zou Fei,Zhao Guifang,Jiang Yixu,Liu Li,Shi Jiahong,Hao Deshun,Zhang Qi,Zheng Tong,Zhang Yingyao,Liu Mingsheng,Li Shilun,Qi Liangchen,Liu Jin Yu Stem cells and development The maintenance of highly proliferative capacity and full differentiation potential is a necessary step in the initiation of stem cell-based regenerative medicine. Our recent study showed that epidermal growth factor (EGF) significantly enhanced hair follicle-derived mesenchymal stem cell (HF-MSC) proliferation while maintaining the multilineage differentiation potentials. However, the underlying mechanism remains unclear. Herein, we investigated the role of EGF in HF-MSC proliferation. HF-MSCs were isolated and cultured with or without EGF. Immunofluorescence staining, flow cytometry, cytochemistry, and western blotting were used to assess proliferation, cell signaling pathways related to the EGF receptor (EGFR), and cell cycle progression. HF-MSCs exhibited surface markers of mesenchymal stem cells and displayed trilineage differentiation potentials toward adipocytes, chondrocytes, and osteoblasts. EGF significantly increased HF-MSC proliferation as well as EGFR, ERK1/2, and AKT phosphorylation (p-EGFR, p-ERK1/2, and p-AKT) in a time- and dose-dependent manner, but not STAT3 phosphorylation. EGFR inhibitor (AG1478), PI3K-AKT inhibitor (LY294002), ERK inhibitor (U0126), and STAT3 inhibitor (STA-21) significantly blocked EGF-induced HF-MSC proliferation. Moreover, AG1478, LY294002, and U0126 significantly decreased p-EGFR, p-AKT, and p-ERK1/2 expression. EGF shifted HF-MSCs at the G1 phase to the S and G2 phase. Concomitantly, cyclinD1, phosphorylated Rb, and E2F1expression increased, while that of p16 decreased. In conclusion, EGF induces HF-MSC proliferation through the EGFR/ERK and AKT pathways, but not through STAT-3. The G1/S transition was stimulated by upregulation of cyclinD1 and inhibition of p16 expression. 10.1089/scd.2016.0234
    Vascular Endothelial Growth Factor Protects CD200-Rich and CD34-Positive Hair Follicle Stem Cells Against Androgen-Induced Apoptosis Through the Phosphoinositide 3-Kinase/Akt Pathway in Patients With Androgenic Alopecia. Zhang Xuesong,Zhou Dongmei,Ma Tengfei,Liu Qingquan Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.] BACKGROUND:5α-DHT can decrease the cell viability of the hair follicle stem cells (HFSCs) with CD34-positive and CD200-rich in bald scalp area of androgenic alopecia (AGA) patients and the apoptosis of HFSCs may be involved in the pathogenesis of AGA. The expression of Vascular endothelial growth factor (VEGF) turns to be weakened or disappeared in hair follicles of AGA patients. OBJECTIVE:To investigate whether VEGF is involved in the apoptosis of HFSCs induced by 5α-DHT in the patients of AGA. METHODS:By 5α-DHT, apoptosis of CD200-rich and CD34-positive HFSCs was induced and apoptotic rates up to 24 hours were assessed using flow cytometry. The expression grades of Bcl-2, Akt, caspase-3 and Bax were observed through Western blot analysis. RESULTS:Vascular endothelial growth factor could cut 5α-DHT induced apoptosis down substantially in a concentration-dependent manner. The 5α-DHT induced decline in the rise of Bcl-2/Bax proportion and the increase in caspase-3 degrees were mostly reversed by using VEGF and the VEGF's anti-apoptotic actions were impeded through preventing the activation of phosphoinositide 3-kinase (PI3K)/Akt. CONCLUSION:Vascular endothelial growth factor can protect CD200-rich and CD34-positive HFSCs from androgen induced apoptosis by means of the PI3K/Akt pathway. 10.1097/DSS.0000000000002091
    Overexpression of Nanog in amniotic fluid-derived mesenchymal stem cells accelerates dermal papilla cell activity and promotes hair follicle regeneration. Park Junghyun,Jun Eun Kyoung,Son Daryeon,Hong Wonjun,Jang Jihoon,Yun Wonjin,Yoon Byung Sun,Song Gwonhwa,Kim In Yong,You Seungkwon Experimental & molecular medicine Alopecia, one of the most common chronic diseases, can seriously affect a patient's psychosocial life. Dermal papilla (DP) cells serve as essential signaling centers in the regulation of hair growth and regeneration and are associated with crosstalk between autocrine/paracrine factors and the surrounding environment. We previously demonstrated that amniotic fluid-derived mesenchymal stem cell-conditioned medium (AF-MSC-CM) accelerates hair regeneration and growth. The present study describes the effects of overexpression of a reprogramming factor, Nanog, on MSC properties, the paracrine effects on DP cells, and in vivo hair regrowth. First, we examined the in vitro proliferation and lifespan of AF-MSCs overexpressing reprogramming factors, including Oct4, Nanog, and Lin28, alone or in combination. Among these factors, Nanog was identified as a key factor in maintaining the self-renewal capability of AF-MSCs by delaying cellular senescence, increasing the endogenous expression of Oct4 and Sox2, and preserving stemness. Next, we evaluated the paracrine effects of AF-MSCs overexpressing Nanog (AF-N-MSCs) by monitoring secretory molecules related to hair regeneration and growth (IGF, PDGF, bFGF, and Wnt7a) and proliferation of DP cells. In vivo studies revealed that CM derived from AF-N-MSCs (AF-N-CM) accelerated the telogen-to-anagen transition in hair follicles (HFs) and increased HF density. The expression of DP and HF stem cell markers and genes related to hair induction were higher in AF-N-CM than in CM from AF-MSCs (AF-CM). This study suggests that the secretome from autologous MSCs overexpressing Nanog could be an excellent candidate as a powerful anagen inducer and hair growth stimulator for the treatment of alopecia. 10.1038/s12276-019-0266-7
    Hair Follicle Development in Mouse Pluripotent Stem Cell-Derived Skin Organoids. Lee Jiyoon,Bӧscke Robert,Tang Pei-Ciao,Hartman Byron H,Heller Stefan,Koehler Karl R Cell reports The mammalian hair follicle arises during embryonic development from coordinated interactions between the epidermis and dermis. It is currently unclear how to recapitulate hair follicle induction in pluripotent stem cell cultures for use in basic research studies or in vitro drug testing. To date, generation of hair follicles in vitro has only been possible using primary cells isolated from embryonic skin, cultured alone or in a co-culture with stem cell-derived cells, combined with in vivo transplantation. Here, we describe the derivation of skin organoids, constituting epidermal and dermal layers, from a homogeneous population of mouse pluripotent stem cells in a 3D culture. We show that skin organoids spontaneously produce de novo hair follicles in a process that mimics normal embryonic hair folliculogenesis. This in vitro model of skin development will be useful for studying mechanisms of hair follicle induction, evaluating hair growth or inhibitory drugs, and modeling skin diseases. 10.1016/j.celrep.2017.12.007
    Feasibility of human hair follicle-derived mesenchymal stem cells/CultiSpher(®)-G constructs in regenerative medicine. Li Pengdong,Liu Feilin,Wu Chunling,Jiang Wenyue,Zhao Guifang,Liu Li,Bai Tingting,Wang Li,Jiang Yixu,Guo Lili,Qi Xiaojuan,Kou Junna,Fan Ruirui,Hao Deshun,Lan Shaowei,Li Yulin,Liu Jin Yu Cell and tissue research The use of human mesenchymal stem cells (hMSCs) in cell therapies has increased the demand for strategies that allow efficient cell scale-up. Preliminary data on the three-dimensional (3D) spinner culture describing the potential use of microcarriers for hMSCs culture scale-up have been reported. We exploited a rich source of autologous stem cells (human hair follicle) and demonstrated the robust in vitro long-term expansion of human hair follicle-derived mesenchymal stem cells (hHF-MSCs) by using CultiSpher(®)-G microcarriers. We analyzed the feasibility of 3D culture by using hHF-MSCs/CultiSpher(®)-G microcarrier constructs for its potential applicability in regenerative medicine by comparatively analyzing the performance of hHF-MSCs adhered to the CultiSpher(®)-G microspheres in 3D spinner culture and those grown on the gelatin-coated plastic dishes (2D culture), using various assays. We showed that the hHF-MSCs seeded at various densities quickly adhered to and proliferated well on the microspheres, thus generating at least hundreds of millions of hHF-MSCs on 1 g of CultiSpher(®)-G within 12 days. This resulted in a cumulative cell expansion of greater than 26-fold. Notably, the maximum and average proliferation rates in 3D culture were significantly greater than that of the 2D culture. However, the hHF-MSCs from both the cultures retained surface marker and nestin expression, proliferation capacity and differentiation potentials toward adipocytes, osteoblasts and smooth muscle cells and showed no significant differences as evidenced by Edu incorporation, cell cycle, colony formation, apoptosis, biochemical quantification and qPCR assays. 10.1007/s00441-015-2182-z
    iRhom2 (Uncv) mutation blocks bulge stem cells assuming the fate of hair follicle. Yang Leilei,Li Wenlong,Liu Bing,Wang Shaoxia,Zeng Lin,Zhang Cuiping,Li Yang Archives of dermatological research iRhom2 is necessary for maturation of TNFα-converting enzyme, which is required for the release of tumor necrosis factor. In the previous study, we found that the iRhom2 (Uncv) mutation in N-terminal cytoplasmic domain-encoding region (iRhom2 (Uncv) ) leads to aberrant hair shaft and inner root sheath differentiation, thus results in a hairless phenotype in homozygous iRhom2 (Uncv/Uncv) BALB/c mice. In this study, we found iRhom2 mutation decreased hair matrix proliferation, however, iRhom2 (Uncv/Uncv) mice displayed hyperproliferation and hyperkeratosis in the interfollicular epidermis along with hypertrophy in the sebaceous glands. The number of bulge SCs was not altered and the hair follicle cycle is normal in iRhom2 (Uncv/Uncv) mice. The decreased proliferation in hair matrix but increased proliferation in epidermis and sebaceous glands in iRhom2 (Uncv/Uncv) mice may implying that iRhom2 (Uncv) mutation blocks bugle stem cells assuming the fate of hair follicle. This study identifies iRhom2 as a novel regulator for determination of keratinocyte lineages. 10.1007/s00403-016-1663-6
    Gasdermin A3-Mediated Cell Death Causes Niche Collapse and Precocious Activation of Hair Follicle Stem Cells. Li Shao-Ting,Suen Wei-Jeng,Kao Cheng-Heng,Yang Ming-Kai,Yang Liang-Tung The Journal of investigative dermatology Hair follicles undergo recurrent growth, regression, and resting phases throughout postnatal life, which is supported by hair follicle stem cells. The niche components of hair follicle stem cells are important to maintain their quiescence and stemness. Gsdma3 gain-of-function mutations in mice cause chronic skin inflammation, aberrant hair cycle, and progressive hair loss, reminiscent of scarring alopecia in humans. However, the mechanism underlying these defects remains elusive. Here, we used a combined Cre/loxP and rtTA/TRE system to study the spatiotemporal effect of Gsdma3 overexpression on distinct hair cycle stages. We found that Gsdma3-mediated cell death affects anagen initiation, anagen progression, and catagen-telogen transition. Induced Gsdma3 expression causes bulge inner layer collapse and precocious hair follicle stem cell activation, leading to subsequent hair follicle degeneration. Although macrophages and dendritic cells are recruited to the bulge region, in vivo depletion of these cells using a neutralizing antibody does not alleviate cell death in the bulge or hair germ, indicating that macrophages are less likely to cause immediate hair follicle deletion. Our data suggest that dysregulated Gsdma3 causes bulge inner layer necrosis to induce club hair shedding and immediate anagen reentry without going through telogen morphology, which implicates a role for Gsdma3 in hair follicle stem cell niche maintenance. 10.1016/j.jid.2020.02.033
    Hair follicle dermal stem cells regenerate the dermal sheath, repopulate the dermal papilla, and modulate hair type. Rahmani Waleed,Abbasi Sepideh,Hagner Andrew,Raharjo Eko,Kumar Ranjan,Hotta Akitsu,Magness Scott,Metzger Daniel,Biernaskie Jeff Developmental cell The dermal papilla (DP) provide instructive signals required to activate epithelial progenitors and initiate hair follicle regeneration. DP cell numbers fluctuate over the hair cycle, and hair loss is associated with gradual depletion/atrophy of DP cells. How DP cell numbers are maintained in healthy follicles remains unclear. We performed in vivo fate mapping of adult hair follicle dermal sheath (DS) cells to determine their lineage relationship with DP and found that a subset of DS cells are retained following each hair cycle, exhibit self-renewal, and repopulate the DS and the DP with new cells. Ablating these hair follicle dermal stem cells and their progeny retarded hair regrowth and altered hair type specification, suggesting that they function to modulate normal DP function. This work identifies a bipotent stem cell within the adult hair follicle mesenchyme and has important implications toward restoration of hair growth after injury, disease, and aging. 10.1016/j.devcel.2014.10.022
    An Intrinsic Oscillation of Gene Networks Inside Hair Follicle Stem Cells: An Additional Layer That Can Modulate Hair Stem Cell Activities. Daszczuk Patrycja,Mazurek Paula,Pieczonka Tomasz D,Olczak Alicja,Boryń Łukasz M,Kobielak Krzysztof Frontiers in cell and developmental biology This article explores and summarizes recent progress in and the characterization of main players in the regulation and cyclic regeneration of hair follicles. The review discusses current views and discoveries on the molecular mechanisms that allow hair follicle stem cells (hfSCs) to synergistically integrate homeostasis during quiescence and activation. Discussion elaborates on a model that shows how different populations of skin stem cells coalesce intrinsic and extrinsic mechanisms, resulting in the maintenance of stemness and hair regenerative potential during an organism's lifespan. Primarily, we focus on the question of how the intrinsic oscillation of gene networks in hfSCs sense and respond to the surrounding niche environment. The review also investigates the existence of a cell-autonomous mechanism and the reciprocal interactions between molecular signaling axes in hfSCs and niche components, which demonstrates its critical driving force in either the activation of whole mini-organ regeneration or quiescent homeostasis maintenance. These exciting novel discoveries in skin stem cells and the surrounding niche components propose a model of the intrinsic stem cell oscillator which is potentially instructive for translational regenerative medicine. Further studies, deciphering of the distribution of molecular signals coupled with the nature of their oscillation within the stem cells and niche environments, may impact the speed and efficiency of various approaches that could stimulate the development of self-renewal and cell-based therapies for hair follicle stem cell regeneration. 10.3389/fcell.2020.595178
    Msi2 Maintains Quiescent State of Hair Follicle Stem Cells by Directly Repressing the Hh Signaling Pathway. Ma Xianghui,Tian Yuhua,Song Yongli,Shi Jianyun,Xu Jiuzhi,Xiong Kai,Li Jia,Xu Wenjie,Zhao Yiqiang,Shuai Jianwei,Chen Lei,Plikus Maksim V,Lengner Christopher J,Ren Fazheng,Xue Lixiang,Yu Zhengquan The Journal of investigative dermatology Hair follicles (HFs) undergo precisely regulated cycles of active regeneration (anagen), involution (catagen), and relative quiescence (telogen). Hair follicle stem cells (HFSCs) play important roles in regenerative cycling. Elucidating mechanisms that govern HFSC behavior can help uncover the underlying principles of hair development, hair growth disorders, and skin cancers. RNA-binding proteins of the Musashi (Msi) have been implicated in the biology of different stem cell types, yet they have not been studied in HFSCs. Here we utilized gain- and loss-of-function mouse models to demonstrate that forced MSI2 expression retards anagen entry and consequently delays hair growth, whereas loss of Msi2 enhances hair regrowth. Furthermore, our findings show that Msi2 maintains quiescent state of HFSCs in the process of the telogen-to-anagen transition. At the molecular level, our unbiased transcriptome profiling shows that Msi2 represses Hedgehog signaling activity and that Shh is its direct target in the hair follicle. Taken together, our findings reveal the importance of Msi2 in suppressing hair regeneration and maintaining HFSC quiescence. The previously unreported Msi2-Shh-Gli1 pathway adds to the growing understanding of the complex network governing cyclic hair growth. 10.1016/j.jid.2017.01.012
    Hair follicle dermal stem cells and skin-derived precursor cells: Exciting tools for endogenous and exogenous therapies. Agabalyan Natacha A,Rosin Nicole L,Rahmani Waleed,Biernaskie Jeff Experimental dermatology Understanding the cellular interactions and molecular signals underlying hair follicle (HF) regeneration may have significant implications for restorative therapies for skin disease that diminish hair growth, whilst also serving to provide fundamental insight into the mechanisms underlying adult tissue regeneration. One of the major, yet underappreciated, players in this process is the underlying HF mesenchyme. Here, we provide an overview of a mesenchymal progenitor pool referred to as hair follicle dermal stem cells (hfDSCs), discuss their potential functions within the skin and their relationship to skin-derived precursors (SKPs), and consider unanswered questions about the function of these specialized fibroblasts. We contend that dermal stem cells provide an important reservoir of renewable dermal progenitors that may enable development of novel restorative therapies following hair loss, skin injury or disease. 10.1111/exd.13359
    Platelet sonicates activate hair follicle stem cells and mediate enhanced hair follicle regeneration. Zhu Meishu,Kong Deqiang,Tian Ruiyun,Pang Mengru,Mo Miaohua,Chen Yu,Yang Guang,Liu Cheng Hanghang,Lei Xiaoxuan,Fang Kunwu,Cheng Biao,Wu Yaojiong Journal of cellular and molecular medicine An increasing number of studies show that platelet-rich plasma (PRP) is effective for androgenic alopecia (AGA). However, the underlying cellular and molecular mechanisms along with its effect on hair follicle stem cells are poorly understood. In this study, we designed to induce platelets in PRP to release factors by calcium chloride (PC) or by sonication where platelet lysates (PS) or the supernatants of platelet lysate (PSS) were used to evaluate their effect on the hair follicle activation and regeneration. We found that PSS and PS exhibited a superior effect in activating telogen hair follicles than PC. In addition, PSS injection into the skin activated quiescent hair follicles and induced K15 hair follicle stem cell proliferation in K14-H2B-GFP mice. Moreover, PSS promoted skin-derived precursor (SKP) survival in vitro and enhanced hair follicle formation in vivo. In consistence, protein array analysis of different PRP preparations revealed that PSS contained higher levels of 16 growth factors (out of 41 factors analysed) than PC, many of them have been known to promote hair follicle regeneration. Thus, our data indicate that sonicated PRP promotes hair follicle stem cell activation and de novo hair follicle regeneration. 10.1111/jcmm.14873
    Activating Hair Follicle Stem Cells via R-spondin2 to Stimulate Hair Growth. Smith Andrew A,Li Jingtao,Liu Bo,Hunter Daniel,Pyles Malcolm,Gillette Martin,Dhamdhere Girija R,Abo Arie,Oro Anthony,Helms Jill A The Journal of investigative dermatology Wnt signaling is required for the development of the hair follicle, and for inciting the growth (anagen) phase of the hair cycle. Most strategies to enhance Wnt signaling for hair growth create a state of constitutive Wnt activation, which leads to neoplastic transformation of the epithelial hair matrix. Using Axin2(LacZ/+) and Axin2(Cre/+)R26R(mTmG/+) reporter mice and RNA analyses, we show that Wnt signaling is elevated during anagen, is reduced at the onset of catagen, and can be reamplified in the skin and surrounding hair follicles via intradermal injection of recombinant R-spondin2 protein. Using Lgr5(LacZ/+) reporter mice, we demonstrate that this amplified Wnt environment leads to activation of leucine-rich repeat-containing G-protein coupled receptor 5-positive stem cells in the hair follicle. The onset of catagen is repressed by R-spondin2 injection, and the anagen phase persists. As a consequence, hair shafts grow longer. We conclude that R-spondin2 treatment activates hair follicle stem cells and therefore may have therapeutic potential to promote hair growth. 10.1016/j.jid.2016.01.041
    Exploring differentially expressed genes between anagen and telogen secondary hair follicle stem cells from the Cashmere goat (Capra hircus) by RNA-Seq. He Nimantana,Su Rui,Wang Zhiying,Zhang Yanjun,Li Jinquan PloS one Hair follicle stem cells (HFSCs) have been shown to be essential in the development and regeneration of hair follicles (HFs). The Inner Mongolia Cashmere goat (Capra hircus) has two types of HFs, primary and secondary, with cashmere being produced from the secondary hair follicle. To identify the genes associated with cashmere growth, transcriptome profiling of anagen and telogen secondary HFSCs was performed by RNA-Seq. The RNA-Seq analysis generated over 58 million clean reads from each group, with 2717 differentially expressed genes (DEGs) detected between anagen and telogen, including 1500 upregulated and 1217 downregulated DEGs. A large number of DEGs were predominantly associated with cell part, cellular process, binding, biological regulation and organelle. In addition, the PI3K-Akt, MAPK, Ras and Rap1 signaling pathways may be involved in the growth of HFSCs cultured in vitro. The RNA-Seq results showed that the well-defined HFSC signature genes and cell cycle-associated genes showed no significant differences between anagen and telogen HFSCs, indicating a relatively quiescent cellular state of the HFSCs cultured in vitro. These results are useful for future studies of complex molecular mechanisms of hair follicle cycling in cashmere goats. 10.1371/journal.pone.0231376
    A Subset of TREM2 Dermal Macrophages Secretes Oncostatin M to Maintain Hair Follicle Stem Cell Quiescence and Inhibit Hair Growth. Wang Etienne C E,Dai Zhenpeng,Ferrante Anthony W,Drake Charles G,Christiano Angela M Cell stem cell Hair growth can be induced from resting mouse hair follicles by topical application of JAK inhibitors, suggesting that JAK-STAT signaling is required for maintaining hair follicle stem cells (HFSCs) in a quiescent state. Here, we show that Oncostatin M (OSM), an IL-6 family cytokine, negatively regulates hair growth by signaling through JAK-STAT5 to maintain HFSC quiescence. Genetic deletion of the OSM receptor or STAT5 can induce premature HFSC activation, suggesting that the resting telogen stage is actively maintained by the hair follicle niche. Single-cell RNA sequencing revealed that the OSM source is not intrinsic to the hair follicle itself and is instead a subset of TREM2 macrophages that is enriched within the resting follicle and deceases immediately prior to HFSC activation. In vivo inhibition of macrophage function was sufficient to induce HFSC proliferation and hair cycle induction. Together these results clarify how JAK-STAT signaling actively inhibits hair growth. 10.1016/j.stem.2019.01.011
    Advances in Regenerative Stem Cell Therapy in Androgenic Alopecia and Hair Loss: Wnt pathway, Growth-Factor, and Mesenchymal Stem Cell Signaling Impact Analysis on Cell Growth and Hair Follicle Development. Gentile Pietro,Garcovich Simone Cells The use of stem cells has been reported to improve hair regrowth in several therapeutic strategies, including reversing the pathological mechanisms, that contribute to hair loss, regeneration of hair follicles, or creating hair using the tissue-engineering approach. Although various promising stem cell approaches are progressing via pre-clinical models to clinical trials, intraoperative stem cell treatments with a one-step procedure offer a quicker result by incorporating an autologous cell source without manipulation, which may be injected by surgeons through a well-established clinical practice. Many authors have concentrated on adipose-derived stromal vascular cells due to their ability to separate into numerous cell genealogies, platelet-rich plasma for its ability to enhance cell multiplication and neo-angiogenesis, as well as human follicle mesenchymal stem cells. In this paper, the significant improvements in intraoperative stem cell approaches, from in vivo models to clinical investigations, are reviewed. The potential regenerative instruments and functions of various cell populaces in the hair regrowth process are discussed. The addition of Wnt signaling in dermal papilla cells is considered a key factor in stimulating hair growth. Mesenchymal stem cell-derived signaling and growth factors obtained by platelets influence hair growth through cellular proliferation to prolong the anagen phase (FGF-7), induce cell growth (ERK activation), stimulate hair follicle development (β-catenin), and suppress apoptotic cues (Bcl-2 release and Akt activation). 10.3390/cells8050466
    Axin2 marks quiescent hair follicle bulge stem cells that are maintained by autocrine Wnt/β-catenin signaling. Lim Xinhong,Tan Si Hui,Yu Ka Lou,Lim Sophia Beng Hui,Nusse Roeland Proceedings of the National Academy of Sciences of the United States of America How stem cells maintain their identity and potency as tissues change during growth is not well understood. In mammalian hair, it is unclear how hair follicle stem cells can enter an extended period of quiescence during the resting phase but retain stem cell potential and be subsequently activated for growth. Here, we use lineage tracing and gene expression mapping to show that the Wnt target gene Axin2 is constantly expressed throughout the hair cycle quiescent phase in outer bulge stem cells that produce their own Wnt signals. Ablating Wnt signaling in the bulge cells causes them to lose their stem cell potency to contribute to hair growth and undergo premature differentiation instead. Bulge cells express secreted Wnt inhibitors, including Dickkopf (Dkk) and secreted frizzled-related protein 1 (Sfrp1). However, the Dickkopf 3 (Dkk3) protein becomes localized to the Wnt-inactive inner bulge that contains differentiated cells. We find that Axin2 expression remains confined to the outer bulge, whereas Dkk3 continues to be localized to the inner bulge during the hair cycle growth phase. Our data suggest that autocrine Wnt signaling in the outer bulge maintains stem cell potency throughout hair cycle quiescence and growth, whereas paracrine Wnt inhibition of inner bulge cells reinforces differentiation. 10.1073/pnas.1601599113
    Effects of Imiquimod on Hair Follicle Stem Cells and Hair Cycle Progression. Amberg Nicole,Holcmann Martin,Stulnig Gabriel,Sibilia Maria The Journal of investigative dermatology Topical imiquimod (IMQ) application is widely used as a model for psoriasiform-like skin inflammation in mice. Although the effects on the epidermis are well characterized, it is unclear how IMQ affects hair follicles and cycling. Here we investigated how IMQ affects hair follicle stem cells and whether the timing of IMQ application influences the immune infiltrate. Our results show that IMQ application at mid and late telogen activated hair follicle stem cells leading to premature hair cycle entry (anagen), which was accompanied by massive infiltration of inflammatory macrophages and gamma delta T cells, whereas the number of the respective resident populations decreased. Interestingly, high resident macrophage numbers were present in Rag2 mice and were maintained after IMQ treatment explaining why IMQ-induced anagen was reduced. This could be rescued after macrophage depletion suggesting that resident macrophages inhibit whereas inflammatory infiltrating macrophages stimulate hair follicle stem cell activation. The expression of the anagen-inhibiting factor BMP-4 was reduced by IMQ treatment as well as the activating factors Wnt showing that IMQ-induced hair follicle stem cell activation occurs by a Wnt-independent mechanism involving inflammatory cytokines such as CCL2 and TNF-α. On the basis of our findings, we recommend conducting experiments with IMQ during mid and late telogen as the biggest differences in immune cell composition are observed. 10.1016/j.jid.2016.06.613
    Neural Stem Cells Restore Hair Growth Through Activation of the Hair Follicle Niche. Hwang Insik,Choi Kyung-Ah,Park Hang-Soo,Jeong Hyesun,Kim Jeong-Ok,Seol Ki-Cheon,Kwon Han-Jin,Park In-Hyun,Hong Sunghoi Cell transplantation Several types of hair loss result from the inability of hair follicles to initiate the anagen phase of the hair regeneration cycle. Modulating signaling pathways in the hair follicle niche can stimulate entry into the anagen phase. Despite much effort, stem cell-based or pharmacological therapies to activate the hair follicle niche have not been successful. Here, we set out to test the effect of neural stem cell (NSC) extract on the hair follicle niche for hair regrowth. NSC extracts were applied to the immortalized cell lines HaCaT keratinocytes and dermal papilla cells (DPCs) and the shaven dorsal skin of mice. Treatment with NSC extract dramatically improved the growth of HaCaT keratinocytes and DPCs. In addition, NSC extract enhanced the hair growth of the shaven dorsal skin of mice. In order to determine the molecular signaling pathways regulated by NSCs, we evaluated the expression levels of multiple growth and signaling factors, such as insulin-like growth factor-1 (IGF-1), hepatocyte growth factor (HGF), keratinocyte growth factor (KGF), vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), and bone morphogenetic protein (BMP) family members. We found that treatment with an NSC extract enhanced hair growth by activating hair follicle niches via coregulation of TGF-β and BMP signaling pathways in the telogen phase. We also observed activation and differentiation of intrafollicular hair follicle stem cells, matrix cells, and extrafollicular DPCs in vivo and in vitro. We tested whether activation of growth factor pathways is a major effect of NSC treatment on hair growth by applying the growth factors to mouse skin. Combined growth factors, including TGF-β, significantly increased the hair shaft length and growth rate. DNA damage and cell death were not observed in skin cells of mice treated with the NSC extract for a prolonged period. Overall, our data demonstrate that NSC extract provides an effective approach for promoting hair growth by directly regulating hair follicle niches through TGF-β and BMP signaling pathways as well as induction of core growth factors. 10.3727/096368916X691466
    Isolation of Mouse Hair Follicle Bulge Stem Cells and Their Functional Analysis in a Reconstitution Assay. Zheng Ying,Hsieh Jen-Chih,Escandon Julia,Cotsarelis George Methods in molecular biology (Clifton, N.J.) The hair follicle (HF) is a dynamic structure readily accessible within the skin, and contains various pools of stem cells that have a broad regenerative potential during normal homeostasis and in response to injury. Recent discoveries demonstrating the multipotent capabilities of hair follicle stem cells and the easy access to skin tissue make the HF an attractive source for isolating stem cells and their subsequent application in tissue engineering and regenerative medicine. Here, we describe the isolation and purification of hair follicle bulge stem cells from mouse skin, and hair reconstitution assays that allows the functional analysis of multipotent stem cells. 10.1007/978-1-4939-3786-8_8
    β-catenin activation in hair follicle dermal stem cells induces ectopic hair outgrowth and skin fibrosis. Tao Yixin,Yang Qingchun,Wang Lei,Zhang Jie,Zhu Xuming,Sun Qianqian,Han Yunbin,Luo Qian,Wang Yushu,Guo Xizhi,Wu Ji,Li Baojie,Yang Xiao,He Lin,Ma Gang Journal of molecular cell biology Hair follicle dermal sheath (DS) harbors hair follicle dermal stem cells (hfDSCs), which can be recruited to replenish DS and dermal papilla (DP). Cultured DS cells can differentiate into various cell lineages in vitro. However, it is unclear how its plasticity is modulated in vivo. Wnt/β-catenin signaling plays an important role in maintaining stem cells of various lineages and is required for HF development and regeneration. Here we report that activation of β-catenin in DS generates ectopic HF outgrowth (EF) by reprogramming HF epidermal cells and DS cells themselves, and endows DS cells with hair inducing ability. Epidermal homeostasis of pre-existing HFs is disrupted. Additionally, cell-autonomous progressive skin fibrosis is prominent in dermis, where the excessive fibroblasts largely originate from DS. Gene expression analysis of purified DS cells with activated β-catenin revealed significantly increased expression of Bmp, Fgf, and Notch ligands and administration of Bmp, Fgf, or Notch signaling inhibitor attenuates EF formation. In summary, our findings advance the current knowledge of high plasticity of DS cells and provide an insight into understanding how Wnt/β-catenin signaling controls DS cell behaviors. 10.1093/jmcb/mjy032
    Functional complexity of hair follicle stem cell niche and therapeutic targeting of niche dysfunction for hair regeneration. Chen Chih-Lung,Huang Wen-Yen,Wang Eddy Hsi Chun,Tai Kang-Yu,Lin Sung-Jan Journal of biomedical science Stem cell activity is subject to non-cell-autonomous regulation from the local microenvironment, or niche. In adaption to varying physiological conditions and the ever-changing external environment, the stem cell niche has evolved with multifunctionality that enables stem cells to detect these changes and to communicate with remote cells/tissues to tailor their activity for organismal needs. The cyclic growth of hair follicles is powered by hair follicle stem cells (HFSCs). Using HFSCs as a model, we categorize niche cells into 3 functional modules, including signaling, sensing and message-relaying. Signaling modules, such as dermal papilla cells, immune cells and adipocytes, regulate HFSC activity through short-range cell-cell contact or paracrine effects. Macrophages capacitate the HFSC niche to sense tissue injury and mechanical cues and adipocytes seem to modulate HFSC activity in response to systemic nutritional states. Sympathetic nerves implement the message-relaying function by transmitting external light signals through an ipRGC-SCN-sympathetic circuit to facilitate hair regeneration. Hair growth can be disrupted by niche pathology, e.g. dysfunction of dermal papilla cells in androgenetic alopecia and influx of auto-reacting T cells in alopecia areata and lichen planopilaris. Understanding the functions and pathological changes of the HFSC niche can provide new insight for the treatment of hair loss. 10.1186/s12929-020-0624-8
    Priming mobilization of hair follicle stem cells triggers permanent loss of regeneration after alkylating chemotherapy. Kim Jin Yong,Ohn Jungyoon,Yoon Ji-Seon,Kang Bo Mi,Park Minji,Kim Sookyung,Lee Woochan,Hwang Sungjoo,Kim Jong-Il,Kim Kyu Han,Kwon Ohsang Nature communications The maintenance of genetic integrity is critical for stem cells to ensure homeostasis and regeneration. Little is known about how adult stem cells respond to irreversible DNA damage, resulting in loss of regeneration in humans. Here, we establish a permanent regeneration loss model using cycling human hair follicles treated with alkylating agents: busulfan followed by cyclophosphamide. We uncover the underlying mechanisms by which hair follicle stem cells (HFSCs) lose their pool. In contrast to immediate destructive changes in rapidly proliferating hair matrix cells, quiescent HFSCs show unexpected massive proliferation after busulfan and then undergo large-scale apoptosis following cyclophosphamide. HFSC proliferation is activated through PI3K/Akt pathway, and depletion is driven by p53/p38-induced cell death. RNA-seq analysis shows that HFSCs experience mitotic catastrophe with G2/M checkpoint activation. Our findings indicate that priming mobilization causes stem cells to lose their resistance to DNA damage, resulting in permanent loss of regeneration after alkylating chemotherapy. 10.1038/s41467-019-11665-0
    Extracellular proteoglycan decorin maintains human hair follicle stem cells. Miyachi Katsuma,Yamada Takaaki,Kawagishi-Hotta Mika,Hasebe Yuichi,Date Yasushi,Hasegawa Seiji,Arima Masaru,Iwata Yohei,Kobayashi Tsukane,Numata Shigeki,Yamamoto Naoki,Nakata Satoru,Sugiura Kazumitsu,Akamatsu Hirohiko The Journal of dermatology Hair follicle stem cells (HFSC) are localized in the bulge region of the hair follicle and play a role in producing hair. Recently, it has been shown that the number of HFSC decreases with age, which is thought to be a cause of senile alopecia. Therefore, maintaining HFSC may be key for the prevention of age-related hair loss, but the regulatory mechanisms of HFSC and the effects of aging on them are largely unknown. In general, stem cells are known to require regulatory factors in the pericellular microenvironment, termed the stem cell niche, to maintain their cell function. In this study, we focused on the extracellular matrix proteoglycan decorin (DCN) as a candidate factor for maintaining the human HFSC niche. Gene expression analysis showed that DCN was highly expressed in the bulge region. We observed decreases in DCN expression as well as the number of KRT15-positive HFSC with age. In vitro experiments with human plucked hair-derived HFSC revealed that HFSC lost their undifferentiated state with increasing passages, and prior to this change a decrease in DCN expression was observed. Furthermore, knockdown of DCN promoted HFSC differentiation. In contrast, when HFSC were cultured on DCN-coated plates, they showed an even more undifferentiated state. From these results, as a novel mechanism for maintaining HFSC, it was suggested that DCN functions as a stem cell niche component, and that the deficit of HFSC maintenance caused by a reduction in DCN expression could be a cause of age-related hair loss. 10.1111/1346-8138.14678
    Hair follicle stem cell proliferation, Akt and Wnt signaling activation in TPA-induced hair regeneration. Qiu Weiming,Lei Mingxing,Zhou Ling,Bai Xiufeng,Lai Xiangdong,Yu Yu,Yang Tian,Lian Xiaohua Histochemistry and cell biology Regeneration of hair follicles relies on activation of hair follicle stem cells during telogen to anagen transition process in hair cycle. This process is rigorously controlled by intrinsic and environmental factors. 12-o-tetradecanoylphorbol-13-acetate (TPA), a tumor promoter, accelerates reentry of hair follicles into anagen phase. However, it is unclear that how TPA promotes the hair regeneration. In the present study, we topically applied TPA onto the dorsal skin of 2-month-old C57BL/6 female mice to examine the activity of hair follicle stem cells and alteration of signaling pathways during hair regeneration. We found that refractory telogen hair follicles entered anagen prematurely after TPA treatment, with the enhanced proliferation of CD34-positive hair follicle stem cells. Meanwhile, we observed Akt signaling was activated in epidermis, hair infundibulum, bulge and hair bulb, and Wnt signaling was also activated after hair follicle stem cells proliferation. Importantly, after overexpression of DKK1, a specific Wnt signaling inhibitor, the accelerated reentry of hair follicles into anagen induced by TPA was abolished. Our data indicated that TPA-induced hair follicle regeneration is associated with activation of Akt and Wnt/β-catenin signaling. 10.1007/s00418-017-1540-1
    Aging in hair follicle stem cells and niche microenvironment. Ji Jiang,Ho Bryan Siu-Yin,Qian Ge,Xie Xiao-Ming,Bigliardi Paul Lorenz,Bigliardi-Qi Mei The Journal of dermatology Hair graying and hair loss are prominent and common characteristics of the elderly population. In some individuals these processes can significantly impact their quality of life, leading to depression, anxiety and other serious mental health problems. Accordingly, there has been much interest in understanding the complex physiological changes within the hair follicle in the aging individual. It is now known that hair follicles represent a prototypical stem cell niche, where both micro- and macroenvironmental influences are integrated alongside stem cell-stem cell and stem cell-stem niche interactions to determine hair growth or hair follicle senescence. Recent studies have identified imbalanced stem cell differentiation and altered stem cell activity as important factors during hair loss, indicating new avenues for the development of therapeutic agents to stimulate hair growth. Here, we pull together the latest findings on the hair follicle stem cell niche and the multifactorial interactions underlying the various forms of hair loss. 10.1111/1346-8138.13897
    Deficiency of Crif1 in hair follicle stem cells retards hair growth cycle in adult mice. Shin Jung-Min,Ko Jung-Woo,Choi Chong-Won,Lee Young,Seo Young-Joon,Lee Jeung-Hoon,Kim Chang-Deok PloS one Hair growth is the cyclically regulated process that is characterized by growing phase (anagen), regression phase (catagen) and resting phase (telogen). Hair follicle stem cells (HFSCs) play pivotal role in the control of hair growth cycle. It has been notified that stem cells have the distinguished metabolic signature compared to differentiated cells, such as the preference to glycolysis rather than mitochondrial respiration. Crif1 is a mitochondrial protein that regulates the synthesis and insertion of oxidative phosphorylation (OXPHOS) polypeptides to inner membrane of mitochondria. Several studies demonstrate that tissue-specific knockout of Crif1 leads to mitochondrial dysfunction. In this study, we investigated the effect of mitochondrial dysfunction in terms of Crif1 deficiency on the hair growth cycle of adult mice. We created two kinds of inducible conditional knockout (icKO) mice. In epidermal specific icKO mice (Crif1 K14icKO), hair growth cycle was significantly retarded compared to wild type mice. Similarly, HFSC specific icKO mice (Crif1 K15icKO) showed significant retardation of hair growth cycle in depilation-induced anagen model. Interestingly, flow cytometry revealed that HFSC populations were maintained in Crif1 K15icKO mice. These results suggest that mitochondrial function in HFSCs is important for the progression of hair growth cycle, but not for maintenance of HFSCs. 10.1371/journal.pone.0232206
    Alkaline Ceramidase 1 Protects Mice from Premature Hair Loss by Maintaining the Homeostasis of Hair Follicle Stem Cells. Lin Chih-Li,Xu Ruijuan,Yi Jae Kyo,Li Fang,Chen Jiang,Jones Evan C,Slutsky Jordan B,Huang Liqun,Rigas Basil,Cao Jian,Zhong Xiaoming,Snider Ashley J,Obeid Lina M,Hannun Yusuf A,Mao Cungui Stem cell reports Ceramides and their metabolites are important for the homeostasis of the epidermis, but much remains unknown about the roles of specific pathways of ceramide metabolism in skin biology. With a mouse model deficient in the alkaline ceramidase (Acer1) gene, we demonstrate that ACER1 plays a key role in the homeostasis of the epidermis and its appendages by controlling the metabolism of ceramides. Loss of Acer1 elevated the levels of various ceramides and sphingoid bases in the skin and caused progressive hair loss in mice. Mechanistic studies revealed that loss of Acer1 widened follicular infundibulum and caused progressive loss of hair follicle stem cells (HFSCs) due to reduced survival and stemness. These results suggest that ACER1 plays a key role in maintaining the homeostasis of HFSCs, and thereby the hair follicle structure and function, by regulating the metabolism of ceramides in the epidermis. 10.1016/j.stemcr.2017.09.015