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Context: The dermal papilla (DP) is a condensation of mesenchymal cells at the proximal end of the hair follicle, which determines hair shaft size and regulates matrix cell proliferation and differentiation. DP cells have the ability to regenerate new hair follicles. These cells tend to aggregate both in vitro and in vivo. This tendency is associated with the ability of papilla cells to induce hair growth. However, human papilla cells lose their hair-inducing activity in later passage number. Ovine DP cells are different from human DP cells since they do not lose their aggregative behavior or hair-inducing activity in culture. Nonetheless, our understanding of ovine DP cells is still limited. Aim: The aim of this study was to observe the expression of established DP markers in ovine cells and their association with aggregation. Subjects and Methods: Ovine DP cells from three different sheep were compared. Histochemistry, immunoflourescence, and polymerase chain reaction experiments were done to analyze the DP markers. Results: We found that ovine DP aggregates expressed all the 16 markers evaluated, including alkaline phosphatase and versican. Expression of the versican V0 and V3 isoforms, neural cell adhesion molecule, and corin was increased significantly with aggregation, while hey-1 expression was significantly decreased. Conclusions: Overall, the stable expression of numerous markers suggests that aggregating ovine DP cells have a similar phenotype to papillae in vivo. The stability of their molecular phenotype is consistent with their robust aggregative behavior and retained follicle-inducing activity after prolonged culture. Their phenotypic stability in culture contrasts with DP cells from other species, and suggests that a better understanding of ovine DP cells might provide opportunities to improve the hair-inducing activity and therapeutic potential of human cells. [ABSTRACT FROM AUTHOR]

Synopsis Objective Mesenchymal-epithelial interactions are important in controlling hair growth and the hair cycle. The β-catenin pathway of dermal papilla cells ( DPCs) plays a pivotal role in morphogenesis and normal regeneration of hair follicles. Deletion of β-catenin in the dermal papilla reduces proliferation of the hair follicle progenitor cells that generate the hair shaft and induces an early onset of the catagen phase. In this study, a modulator of the Wnt/ β-catenin activity was studied in oriental herb extracts on cultured human DPCs. Methods The effect of Malva verticillata ( M. verticillata) seeds on human DPCs was investigated by a Wnt/ β-catenin reporter activity assay system ( β-catenin- TCF/ LEF reporter gene) and cell proliferation analysis. The synthesis of the factors related to hair growth and cycling was measured at both the mRNA and the protein level by semi-quantitative PCR and Western blot analysis, respectively. Results An extract from M. verticillata seeds increased Wnt reporter activity in a concentration-dependent manner and also led to increased β-catenin levels in cultured human DPCs. Myristoleic acid, identified as an effective compound of M. verticillata seeds, stimulated the proliferation of DPCs in a dose-dependent manner and increased transcription levels of the downstream targets: IGF-1, KGF, VEGF and HGF. Myristoleic acid also enhanced the phosphorylation of MAPKs (Akt and p38). Conclusion Overall, the data suggest that this extract of M. verticillata seeds could be a good candidate for treating hair loss by modulating the Wnt/ β-catenin pathway in DPCs. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor 9 ( FGF9 ) is crucial for the growth and development of hair follicles (HFs); however, its role in sheep wool growth is unknown. Here, we clarified the role of FGF9 in HF growth in the small-tailed Han sheep by quantifying FGF9 expression in skin tissue sections collected at different periods. Moreover, we evaluated the effects of FGF9 protein supplementation on hair shaft growth in vitro and FGF9 knockdown on cultured dermal papilla cells (DPCs). The relationship between FGF9 and the Wnt/β-catenin signaling pathway was examined, and the underlying mechanisms of FGF9 -mediated DPC proliferation were investigated. The results show that FGF9 expression varies throughout the HF cycle and participates in wool growth. The proliferation rate and cell cycle of FGF9 -treated DPCs substantially increase compared to that of the control group, and the mRNA and protein expression of CTNNB1 , a Wnt/β-catenin signaling pathway marker gene, is considerably lower than that in the control group. The opposite occurs in FGF9 -knockdown DPCs. Moreover, other signaling pathways are enriched in the FGF9 -treated group. In conclusion, FGF9 accelerates the proliferation and cell cycle of DPCs and may regulate HF growth and development through the Wnt/β-catenin signaling pathway.

Alopecia, regardless of gender, exacerbates psychological stress in those affected. The rising prevalence of alopecia has fueled a research interest in preventing hair loss. This study investigates the potential of millet seed oil (MSO) in promoting the proliferation of hair follicle dermal papilla cells (HFDPC) and stimulating hair growth in animals with testosterone-dependent hair growth inhibition as part of a study on dietary treatments to improve hair growth. MSO-treated HFDPC significantly increased cell proliferation and phosphorylation of AKT, S6K1, and GSK3β proteins. This induces β-catenin, a downstream transcription factor, to translocate to the nucleus and increase the expression of factors related to cell growth. In a C57BL/6 mice model in which hair growth was inhibited by subcutaneous testosterone injection after shaving the dorsal skin, oral administration of MSO stimulated hair growth in the subject mice by increasing the size and number of hair follicles. These results suggest that MSO is a potent agent that may help prevent or treat androgenetic alopecia by promoting hair growth., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lee, Seo, Kim, Park, Kim, Hyun, Hahm, Ha, Ahn and Jung.)

Objective: In this study, we evaluated the effect of scalp massage on hair in Japanese males and the effect of stretching forces on human dermal papilla cells in vitro. Methods: Nine healthy men received 4 minutes of standardized scalp massage per day for 24 weeks using a scalp massage device. Total hair number, hair thickness, and hair growth ratewere evaluated. Themechanical effect of scalpmassage on subcutaneous tissue was analyzed using a finite element method. To evaluate the effect of mechanical forces, human dermal papilla cells were cultured using a 72-hour stretching cycle. Gene expression changewas analyzed using DNA microarray analyses. In addition, expression of hair cycle-related genes including IL6, NOGGIN, BMP4, and SMAD4were evaluated using real-time reverse transcription-polymerase chain reaction. Results: Standardized scalp massage resulted in increased hair thickness 24 weeks after initiation of massage (0.085 ± 0.003 mm vs 0.092 ± 0.001 mm). Finite element method showed that scalp massage caused z-direction displacement and von Mises stress on subcutaneous tissue. In vitro, DNA microarray showed gene expression change significantly compared with nonstretching human dermal papilla cells. A total of 2655 genes were upregulated and 2823 genes were downregulated. Real-time reverse transcription-polymerase chain reaction demonstrated increased expression of hair cycle-related genes such as NOGGIN, BMP4, SMAD4, and IL6ST and decrease in hair loss-related genes such as IL6. Conclusions: Stretching forces result in changes in gene expression in human dermal papilla cells. Standardized scalp massage is a way to transmit mechanical stress to human dermal papilla cells in subcutaneous tissue. Hair thickness was shown to increase with standardized scalp massage. [ABSTRACT FROM AUTHOR]

Dermal papilla (DP) cells function as important regulators of the hair growth cycle. The loss of these cells is a primary cause of diseases characterized by hair loss, including alopecia, and evidence has revealed significantly increased levels of reactive oxygen species (ROS) in hair tissue and DP cells in the balding population. In the present study, troxerutin, a flavonoid derivative of rutin, was demonstrated to have a protective effect against H2O2-mediated cellular damage in human DP (HDP) cells. Biochemical assays revealed that pretreatment with troxerutin exerted a protective effect against H2O2-induced loss of cell viability and H2O2-induced cell death. Further experiments confirmed that troxerutin inhibited the H2O2-induced production of ROS and upregulation of senescence-associated β-galactosidase activity. Using microRNA (miRNA) microarrays, the present study identified 24 miRNAs, which were differentially expressed in the troxerutin-pretreated, H2O2-treated HDP cells. Subsequent prediction using bioinformatics analysis revealed that the altered miRNAs were functionally involved in several cell signaling pathways, including the mitogen-activated protein kinase and WNT pathways. Overall, these results indicated that ROS-mediated cellular damage was inhibited by troxerutin and suggested that the use of troxerutin may be an effective approach in the treatment of alopecia. [ABSTRACT FROM AUTHOR]

This study developed lipid nanocarriers, called squarticles, conjugated with anti-platelet-derived growth factor (PDGF)-receptor β antibody to determine whether targeted Minoxidil (MXD) delivery to the follicles and dermal papilla cells (DPCs) could be achieved. Squalene and hexadecyl palmitate (HP) were used as the matrix of the squarticles. The PDGF-squarticles showed a mean diameter and zeta potential of 195 nm and − 46 mV, respectively. Nanoparticle encapsulation enhanced MXD porcine skin deposition from 0.11 to 0.23 μg/mg. The antibody-conjugated nanoparticles ameliorated follicular uptake of MXD by 3-fold compared to that of the control solution in the in vivo mouse model. Both vertical and horizontal skin sections exhibited a wide distribution of nanoparticles in the follicles, epidermis, and deeper skin strata. The encapsulated MXD moderately elicited proliferation of DPCs and vascular endothelial growth factor (VEGF) expression. The active targeting of PDGF-squarticles may be advantageous to improving the limited success of alopecia therapy. From the Clinical Editor Topical use of minoxidil is only one of the very few treatment options for alopecia. Nonetheless, the current delivery method is far from ideal. In this article, the authors developed lipid nanocarriers with anti-platelet-derived growth factor receptor ? antibody to target dermal papilla cells, and showed enhanced uptake of minoxidil. [ABSTRACT FROM AUTHOR]

Baicalin, a flavonoid isolated from Scutellaria baicalensis, is known to have multiple biological functions. Recent studies have demonstrated that baicalin treatment increases alkaline phosphatase activity (ALP) and osteoprotegerin secretion by osteoblasts. Furthermore, baicalin induces the differentiation of cultured osteoblasts via the activation of the Wnt/β-catenin signaling pathway. In this study, we evaluated the hair growth-promoting effects of baicalin in human follicular dermal papilla (DP) cells. A reporter assay and Western blotting were used to assess the effect of baicalin on β-catenin signaling in DP cells. ALP activity and messenger RNA (mRNA) expression were examined by ALP staining and real-time polymerase chain reaction (PCR), respectively. Growth factor expression levels were also evaluated using real-time PCR. Finally, the effect of baicalin on hair growth in vivo was examined by topical application of baicalin on the shaved dorsal skin of C57BL/6 mice. Our results indicate that baicalin activates Wnt/β-catenin signaling in a dose-dependent manner in human DP cells. ALP mRNA expression and activity were significantly induced in the presence of baicalin. In addition, treatment with baicalin induced the mRNA expression of growth factors, such as insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF). Moreover, compared to vehicle treatment, baicalin treatment induced an earlier conversion from telogen to anagen. Our results strongly suggest that baicalin promotes hair growth by regulating the activity of DP cells. [ABSTRACT FROM AUTHOR]

Background: Finasteride and minoxidil are two commonly used drugs for the treatment of hair loss. However, these two drugs have certain side effects. Thus, the further elucidation of treatments for hair loss, including those using Chinese herbal medicine, remains important clinically. Shi-Bi-Man (SBM) is a hair health supplement that darkens hair and contains ginseng radix, tea polyphenols, polygonum multiflorum, radix angelicae sinensis, aloe, linseed, and green tea extract.Purpose: This study aimed to find potential effective monomer components to promote hair regeneration from SBM and to explore the mechanism of SBM to promote hair regeneration.Methods: Supplementation with the intragastric administration or smear administration of SBM in artificially shaved C57BL/6 mice, observe its hair growth. UPLC/MS and UPLC/LTQ-Orbitrap-MS detect the main components in SBM and the main monomers contained in the skin after smearing, respectively. A network pharmacology study on the main components of SBM and single-cell RNA sequencing was performed to explore the role of SBM for hair regeneration.Results: SBM significantly induced hair growth compared with a control treatment. TSG and EGCG were the main monomers in the skin after SBM smearing. The results of single-cell sequencing revealed that after SBM treatment, the number of hair follicle stem cells (HFSCs) and dermal papilla cells (DPCs) increased significantly. Cell interactions and volcano dots show that the interaction of the FGF signaling pathway was significantly enhanced, in which Fgf7 expression was especially upregulated in DPCs. In addition, the Wnt signaling pathway also had a partially enhanced effect on the interactions between various cells in the skin. The network pharmacology study showed that the promotion of the FGF and Wnt pathways by SBM was also enriched in alopecia diseases.Conclusion: We report that SBM has a potential effect on the promotion of hair growth by mainly activating the FGF signaling pathway. The use of SBM may be a novel therapeutic option for hair loss. [ABSTRACT FROM AUTHOR]

Cacumen Platycladi (CP) consists of the dried needles of Platycladus orientalis L.) Franco. It was clinically demonstrated that it effectively regenerates hair, but the underlying mechanism remains unknown. Thus, we employed shaved mice to verify the hair growth-promoting capability of the water extract of Cacumen Platycladi (WECP). The morphological and histological analyses revealed that WECP application could significantly promote hair growth and hair follicles (HFs) construction, in comparison to that of control group. Additionally, the skin thickness and hair bulb diameter were significantly increased by the application of WECP in a dose-dependent manner. Besides, the high dose of WECP also showed an effect similar to that of finasteride. In an in vitro assay, WECP stimulated dermal papilla cells (DPCs) proliferation and migration. Moreover, the upregulation of cyclins (cyclin D1, cyclin-dependent kinase 2 (CDK2), and cyclin-dependent kinase 4 (CDK4)) and downregulation of P21 in WECP-treated cell assays have been evaluated. We identified the ingredients of WECP using ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) and endeavored to predict their relevant molecular mechanisms by network analysis. We found that the Akt (serine/threonine protein kinase) signaling pathway might be a crucial target of WECP. It has been demonstrated that WECP treatment activated the phosphorylation of Akt and glycogen synthase kinase-3-beta (GSK3β), promoted β-Catenin and Wnt10b accumulation, and upregulated the expression of lymphoid enhancer-binding factor 1 (LEF1), vascular endothelial growth factor (VEGF), and insulin-like growth factor 1 (IGF1). We also found that WECP significantly altered the expression levels of apoptosis-related genes in mouse dorsal skin. The enhancement capability of WECP on DPCs proliferation and migration could be abrogated by the Akt-specific inhibitor MK-2206 2HCl. These results suggested that WECP might promote hair growth by modulating DPCs proliferation and migration through the regulation of the Akt/GSK3β/β-Catenin signaling pathway., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Fu, Li, Weng, Huang, Liu, Mao and Ding.)

Dermal papilla (DP) cells may be the source of dermal-derived signaling molecules involved in hair-follicle development and postnatal hair cycling. Early-passage DP cells can induce hair growth in vivo, but, on further culture, this ability is lost. The cellular mechanisms underlying the hair-follicle induction property of early-passage DP cells are unclear. Long noncoding RNAs (lncRNAs) are an important class of genes involved in various biological functions. They are aberrantly expressed and play roles in the regulation of the Wnt signaling pathway, a critical point in maintaining hair-induction activity. LncRNA microarray revealed 1683 upregulated and 1773 downregulated lncRNAs in passage-4 DP cells compare with passage-10 DP cells. To investigate the relation between lncRNAs and coding genes in WNT signaling, we constructed a coding–noncoding gene co-expression network using lncRNAs and coding genes that were differentially expressed between the passage-4 and -10 DP cells. RP11-766N7.3, H19 and HOTAIR are specific lncRNAs that were aberrantly expressed in DP cells and played an important role in regulating Wnt signaling. This study may provide potential targets for discovering the hair-follicle induction mechanism of early-passage DP cells. [ABSTRACT FROM AUTHOR]

7-Phloroeckol, phloroglucinol derivative isolated from marine brown algae, has anti-oxidative, anti-inflammatory responses and MMP inhibitory activities. In this study, we evaluated the hair growth-promoting effects of 7-phloroeckol in human hair follicles. To investigate cell viability of human dermal papilla cells (DPCs) and outer root sheath (ORS) cells in the presence or absence of 7-phloroeckol treatment, MTT assay was employed. Moreover, gene expression and protein concentration of insulin-like growth factor (IGF)-1 was measured by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. 7-Phloroeckol induced an increase in proliferation of DPCs and ORS cells. In addition, hair shaft growth was measured using the hair-follicle organ culture system. 7-Phloroeckol resulted in elongation of the hair shaft in cultured human hair follicles. 7-Phloroeckol induced an IGF-1 mRNA expression and protein concentration in DPCs and conditioned media, respectively. These results suggest that 7-phloroeckol promotes hair growth through stimulation of DPCs and ORS cells. [ABSTRACT FROM AUTHOR]

Abstract: Broad dermal Wnt signaling is required for patterned induction of hair follicle placodes and subsequent Wnt signaling in placode stem cells is essential for induction of dermal condensates, cell clusters of precursors for the hair follicle dermal papilla (DP). Progression of hair follicle formation then requires coordinated signal exchange between dermal condensates and placode stem cells. However, it remains unknown whether continued Wnt signaling in DP precursor cells plays a role in this process, largely due to the long-standing inability to specifically target dermal condensates for gene ablation. Here we use the Tbx18Cre knockin mouse line to ablate the Wnt-responsive transcription factor β-catenin specifically in these cells at E14.5 during the first wave of guard hair follicle formation. In the absence of β-catenin, canonical Wnt signaling is effectively abolished in these cells. Sox2+ dermal condensates initiate normally; however by E16.5 guard hair follicle numbers are strongly reduced and by E18.5 most whiskers and guard hair follicles are absent, suggesting that active Wnt signaling in dermal condensates is important for hair follicle formation to proceed after induction. To explore the molecular mechanisms by which Wnt signaling in dermal condensates regulates hair follicle formation, we analyze genome-wide the gene expression changes in embryonic β-catenin null DP precursor cells. We find altered expression of several signaling pathway genes, including Fgfs and Activin, both previously implicated in hair follicle formation. In summary, these data reveal a functional role of Wnt signaling in DP precursors for embryonic hair follicle formation and identify Fgf and Activin signaling as potential effectors of Wnt signaling-regulated events. [Copyright &y& Elsevier]

Alopecia is an exceedingly prevalent problem effecting men and women of all ages. The standard of care for alopecia involves either transplanting existing hair follicles to bald areas or attempting to stimulate existing follicles with topical and/or oral medication. Yet, these treatment options are fraught with problems of cost, side effects, and, most importantly, inadequate long-term hair coverage. Innovative cell-based therapies have focused on the dermal papilla cell as a way to grow new hair in previously bald areas. However, despite this attention, many obstacles exist, including retention of dermal papilla inducing ability and maintenance of dermal papilla productivity after several passages of culture. The use of adipocyte lineage cells, including adipose-derived stem cells, has shown promise as a cell-based solution to regulate hair regeneration and may help in maintaining or increasing dermal papilla cells inducing hair ability. In this review, we highlight recent advances in the understanding of the cellular contribution and regulation of dermal papilla cells and summarize adipocyte lineage cells in hair regeneration. [ABSTRACT FROM AUTHOR]

Abstract: Glucocorticoid (GC) is synthesized mostly in the adrenal gland and is secreted in response to stressful conditions. The stress-induced increase in systemic GC may mediate diverse types of cellular damage. However, the specific effects of GC on the dermal papilla cells (DPCs) of hair follicles remain unknown, although stress-related hair loss has increased significantly in recent years. The objective of this study was to determine the effect of a synthetic GC, dexamethasone (Dex), on human DPCs in vitro. We evaluated the effects of Dex on cell proliferation, survival, and the expression of growth factors in DPCs. Dex treatment (1μM) significantly reduced the number of viable cells and the expression of the Ki-67 protein, VEGF and HGF were downregulated following treatment of DPCs with Dex. Taken together, we concluded that Dex inhibits human hair growth by inhibiting both the proliferation of, and growth factors expression by, DPCs. [Copyright &y& Elsevier]

Alopecia is a common and distressing medical condition that has affected a majority of people worldwide, which leads to great effects on the quality of life and self-esteem. Numerous treatments had been used to cure alopecia, including hair growth stimulants, herbal products, and hair transplantation. However, these treatments have their side effects, such as hypertrichosis, edema, and even cardiovascular adverse effects, which lead to the urgent requirement to explore a new hair-follicle (HF) regeneration approach. Tissue engineering could be the potential way for HF regeneration by simulating the epithelial-mesenchymal interaction and cell-extracellular matrix interactions. This review summarized the potential cells that are used in tissue engineering, commonly used tissue engineering techniques, and most importantly, the biomaterials that have been applied for in vitro three-dimensional cell culture or in vivo co-transplantation in HF regeneration. The literature shows that advances in this field toward functional HF development have progressively increased. Although the clinical application of biomaterial co-transplantation for HF regeneration still faces various challenges, numerous studies have proved that this is a promising direction that could be achieved in the future., Competing Interests: We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled “The Potential Applications of Biomaterials in Tissue Engineering for Hair Follicles Regeneration”., (© 2022 The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V.)

Abstract: Background: Dermal papilla cells (DPCs), which exhibit a multilayer aggregative growth character in in vitro culture, are closely related to induction of hair follicles (HFs) formation, and are associated with the development and cycle regulation of HFs. Versican, a large chondroitin sulfate proteoglycan and one of the major components of the extracellular matrix, plays an essential role in hair follicle formation. And also the Wnt/β-catenin signaling pathway performs a crutial function in induction during hair follicle growth and embryogenesis. Objective: To characterize the role of versican and β-catenin in regulating DPCs aggregative growth, and to explore the versican gene expression regulation mechanism by TCF-4/β-catenin signaling pathway. Methods: We first cultured DPCs at different passages, and detected the change in β-catenin and versican expression in DPCs of various passages by RT-PCR and Western blot. Then we knockdowned the versican and β-catenin gene, evaluated and verificated the binding capability of TCF-4/β-catenin to TOP elements in versican gene promoter region at varied passage DPCs by EMSA and ChIP Assay, finally observed the effect of Wnt/β-catenin pathway inhibition on DPC aggregative growth. Results: With the increase of passage, DPCs lost the aggregative property, the versican mRNA and protein level in DPCs was on a gradual decline, while not significant declining tendency of β-catenin. The mRNA of both β-catenin and versican reduced simultaneously after β-catenin siRNA transfection. The binding ability of TCF-4/β-catenin of varied-passage DPCs to cultured versican promoters diminished with the increase of DPC passages. And versican inhibition or Wnt/β-catenin pathway blocking could both produce considerable effect on the aggregative growth of low-passage DPCs. Conclusion: Wnt/β-catenin signal transducting system regulates DPC aggregative growth through modifying versican expression by means of acting on the versican gene upstream promoter. [Copyright &y& Elsevier]

This study was conducted to evaluate the effect of Ecklonia cava, a marine alga native to Jeju Island in Korea, on the promotion of hair growth. When vibrissa follicles were cultured in the presence of E. cava enzymatic extract (which contains more than 35% of dieckol) for 21 days, E. cava enzymatic extract increased hair-fiber length. In addition, after topical application of the 0.5% E. cava enzymatic extract onto the back of C57BL/6 mice, anagen progression of the hair-shaft was induced. The treatment with E. cava enzymatic extract resulted in the proliferation of immortalized vibrissa dermal papilla cells (DPC). Especially, dieckol, among the isolated compounds from the E. cava enzymatic extract, showed activity that increased the proliferation of DPC. When NIH3T3 fibroblasts were treated with the E. cava enzymatic extract and the isolated compounds from the E. cava enzymatic extract, the E. cava enzymatic extract increased the proliferation of NIH3T3 fibroblasts, but the isolated compounds such as eckol, dieckol, phloroglucinol and triphlorethol-A did not affect the proliferation of NIH3T3 fibroblasts. On the other hand, the E. cava enzymatic extract and dieckol significantly inhibited 5α-reductase activity. These results suggest that dieckol from E. cava can stimulate hair growth by the proliferation of DPC and/or the inhibition of 5α-reductase activity. [ABSTRACT FROM AUTHOR]

ABSTRACT In previous studies, HSPC016 was identified as a differentially expressed gene in dermal papilla cells (DPC) with aggregative behaviour. To clarify its role in the regulation of DPC, the recombinant HSPC016 protein was expressed using the Pichia pastoris expression system, and three small interfering ribonucleic acid duplexes (siRNA) were designed and transfected into DPC. Results showed that DPC with the HSPC016 gene inhibited, exhibit non-aggregative behaviour and grow much slower than normal DPC, and that the recombinant HSPC016 protein could promote the proliferation of high-passage DPC and induce its aggregative behaviour. [ABSTRACT FROM AUTHOR]

Abstract: Dermal papilla (DP) cells play a regulatory role in hair growth, and also play a role in alopecia (hair loss). However, effects of taxol, which is a widely used chemotherapy drug, on DP cells remain unclear, despite that theoretically taxol can impact on DP cells to contribute to taxol-induced alopecia. To better understand pathophysiology of taxol-induced damage in DP cells, morphological and biochemical analyses were performed to check whether taxol can cause apoptosis in cultured DP cells or not. If it can, proteomics and bioinformatics analyses were then performed to investigate the protein networks which are impacted by the taxol treatment. Our data showed that taxol can cause apoptotic damage in DP cells in a concentration-dependant manner, as demonstrated by various apoptotic markers. Proteomic analysis on DP cells treated with the lowest apoptosis-inducible concentration of taxol revealed that taxol can affect expression of proteins involved in Ca2+-regulated biological processes, vesicles transport, protein folding, reductive detoxification, and biomolecules metabolism. Furthermore, bioinformatics analysis indicated that taxol can impact on multiple biological networks. Taken together, this biochemical, proteomics, and bioinformatics data may give an insight into pathophysiology of taxol-induced damage in DP cells and shed light on mechanisms underlying taxol-induced alopecia. [Copyright &y& Elsevier]

Reprogramming patient-specific somatic cells into induced pluripotent stem (iPS) cells has great potential to develop feasible regenerative therapies. However, several issues need to be resolved such as ease, efficiency, and safety of generation of iPS cells. Many different cell types have been reprogrammed, most conveniently even peripheral blood mononuclear cells. However, they typically require the enforced expression of several transcription factors, posing mutagenesis risks as exogenous genetic material. To reduce this risk, iPS cells were previously generated with Oct4 alone from rather inaccessible neural stem cells that endogenously express the remaining reprogramming factors and very recently from fibroblasts with Oct4 alone in combination with additional small molecules. Here, we exploit that dermal papilla (DP) cells from hair follicles in the skin express all but one reprogramming factors to show that these accessible cells can be reprogrammed into iPS cells with the single transcription factor Oct4 and without further manipulation. Reprogramming was already achieved after 3 weeks and with efficiencies similar to other cell types reprogrammed with four factors. Dermal papilla-derived iPS cells are comparable to embryonic stem cells with respect to morphology, gene expression, and pluripotency. We conclude that DP cells may represent a preferred cell type for reprogramming accessible cells with less manipulation and for ultimately establishing safe conditions in the future by replacing Oct4 with small molecules. STEM CELLS 2011;29:964-971 [ABSTRACT FROM AUTHOR]

In the present work, we labeled human epidermal keratinocytes and dermal papilla cells in order to study their behavior after intradermal transplantation. The cells were transduced by lentiviral vectors that bore a marker gene that encodes green fluorescent protein (copGFP) or red fluorescent protein (DsRed). A portion of the transgene expressing cells was evaluated by flow cytometry. The proposed genetic constructions have allowed one to achieve high efficiency (>95%) of the transduction of hair follicle cells. The in vitro transduced cells were injected under epidermis of human skin fragments, after which these fragments were transplanted under the skin of immunodeficient mice. The injected epidermal keratinocytes were found mainly in hair follicles and partially in the zone of interfollicular epidermis, while dermal papilla cells were found in the papilla of the derma. The results of the present study have shown that the chosen genetic constructions obtained based on human immunodeficiency lentivirus are capable of the effective and stable transduction of human skin cells. The injected cells survived and were found in the corresponding skin structures. [ABSTRACT FROM AUTHOR]

The ability of dermal papilla (DP) cells to induce hair growth was reported in many studies. However, early stages of hair follicle development and signals that govern this process are poorly understood. Therefore, an in vitro model may be a convenient system to study epithelial–mesenchymal interactions and early stages of epidermal morphogenesis, especially in humans. To investigate the role of DP cells in epidermal morphogenesis we modified the method of isolation of DP cells from hair follicle of human scalp and developed the three-dimensional model of epidermal morphogenesis. Isolated DP cells were able to differentiate in adipogenic and osteogenic directions and retained activity of alkaline phosphatase (AP) for seven passages in culture. DP cells were able to induce tubule-like structures in three-dimensional model in vitro and to reorganize collagen matrix. Prolonged cultivation of DP cells has been a big problem because of the loss of hair follicle-inducing ability and growth activity after several passages. To solve this problem we immortalized DP cells by the transfection of the human telomerase reverse transcriptase cDNA (hTERT). Immortalized DP-hTERT cells retained AP activity and demonstrated low ability to osteogenic differentiation. The conditioned medium collected from actively proliferated cells as well as DP-hTERT cells themselves were capable to induce tubulogenesis after prolonged keratinocyte cultivation. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding the potential augmentation of canonical Wnt/β-catenin signalling in cultured dermal papilla (DP) cells in secreted frizzled-related protein 2 (SFRP2).

Abstract: In healthy individuals, skin integrity is maintained by epidermal stem cells which self-renew and generate daughter cells that undergo terminal differentiation. Despite accumulation of senescence markers in aged skin, epidermal stem cells are maintained at normal levels throughout life. Therefore, skin ageing is induced by impaired stem cell mobilisation or reduced number of stem cells able to respond to proliferative signals. In the skin, existence of several distinct stem cell populations has been reported. Genetic labelling studies detected multipotent stem cells of the hair follicle bulge to support regeneration of hair follicles but not been responsible for maintaining interfollicular epidermis, which exhibits a distinct stem cell population. Hair follicle epithelial stem cells have at least a dual function: hair follicle remodelling in daily life and epidermal regeneration whenever skin integrity is severely compromised, e.g. after burns. Bulge cells, the first adult stem cells of the hair follicle been identified, are capable of forming hair follicles, interfollicular epidermis and sebaceous glands. In addition, – at least in murine hair follicles – they can also give rise to non-epithelial cells, indicating a lineage-independent pluripotent character. Multipotent cells (skin-derived precursor cells) are present in human dermis; dermal stem cells represent 0.3% among human dermal foreskin fibroblasts. A resident pool of progenitor cells exists within the sebaceous gland, which is able to differentiate into both sebocytes and interfollicular epidermis. The self-renewal and multi-lineage differentiation of skin stem cells make these cells attractive for ageing process studies but also for regenerative medicine, tissue repair, gene therapy and cell-based therapy with autologous adult stem cells not only in dermatology. In addition, they provide in vitro models to study epidermal lineage selection and its role in the ageing process. [Copyright &y& Elsevier]

Abstract: Androgens regulate hair growth, and 5α-reductase (5αR) plays a pivotal role in the action of androgens on target organs. To clarify the molecular mechanisms responsible for controlling hair growth, the present study presents evidence that the human follicular dermal papilla cells (DPCs) from either beard (bDPCs) or scalp hair (sDPCs) possess endogenous 5αR activity. Real-time RT-PCR revealed that the highest level of 5αR1 mRNA was found in bDPCs, followed by sDPCs, and a low but detectable level of 5αR1 mRNA was observed in fibroblasts. Minimally detectable levels of 5αR2 mRNA were found in all three cell types. A weak band at 26kDa corresponding to the human 5αR1 protein was detected by Western blot in both DPCs, but not in fibroblasts. Immuonofluorescence analysis confirmed that 5αR1 was localized to the cytoplasm rather than in the nuclei in both DPCs Furthermore, a 5αR assay using [14C]testosterone labeling in intact cells revealed that testosterone was transformed primarily into androstenedione, and in small amounts, into DHT. Our results demonstrate that the 5αR activities of either bDPCs or sDPCs are stronger than that of dermal fibroblasts, despite the fact that the major steroidogenic activity is attributed to 17β-HSD rather than 5αR among the three cell types. The 5αR1 inhibitor MK386 exhibited a more potent inhibitory effect on 5αR activity than finasteride (5αR2 inhibitor) in bDPCs. [Copyright &y& Elsevier]

Summary: Background: The dermal papilla is a major component of hair, which signals the follicular epithelial cells to prolong the hair growth process. To date, little is known about the significance of the specific protein(s) express in the dermal papilla cells (DPC) with regard to their aggregative behaviour. Objectives: To identify proteins involved in aggregative behaviour of DPC, we comparatively analyzed the proteome of cells with and without aggregative behaviour. Methods: A series of methods were used, including two-dimensional gel electrophoresis (2-DE), PDQuest software analysis of 2-DE gels, peptide mass fingerprinting based on matrix-assisted laser desorption/ionisation-time of flight-mass spectrometry (MALDI-TOF-MS), and NCBInr database searching, to separate and identify differentially expressed proteins. Western blotting and reverse transcriptase polymerase chain reaction (RT-PCR) were used to validate the differentially expressed proteins. Results: Image analysis revealed that averages of 618±22 and 568±47 protein spots were detected in passages 3 and 10 DPC, respectively. Twenty-four differential protein spots were measured with MALDI-TOF-MS. A total of 17 spots yielded good spectra, and 15 spots matched with known proteins after database searching. Western blotting confirmed that heat shocking protein 70 was up-regulated in passage 3 DPC. Over-expression of mitochondrial ribosomal protein S7 was confirmed by RT-PCR, indicating that they are involved in aggregation of DPC through some signaling pathway. Conclusions: The clues provided by the comparative proteome strategy utilized here will shed light on molecular mechanisms of DPC in aggregative behaviour. [Copyright &y& Elsevier]

The tripeptide-copper complex, described as a growth factor for various kinds of differentiated cells, stimulates the proliferation of dermal fibroblasts and elevates the production of vascular endothelial growth factor, but decreased the secretion of transforming growth factor-β1 by dermal fibroblasts. Dermal papilla cells (DPCs) are specialized fibroblasts, which are important in the morphogenesis and growth of hair follicles. In the present study, the effects of L-alanyl-L-histidy l-L-lysine-Cu2+ (AHK-Cu) on human hair growth ex vivo and cultured dermal papilla cells were evaluated. AHK-Cu (10-12-10-9M) stimulated the elongation of human hair follicles ex vivo and the proliferation of DPCs in vitro. Annexin V-fluorescein isothiocyanate/propidium iodide labeling and flow cytometric analysis showed that 10-9M AHK-Cu reduced the number of apoptotic DPCs, but this decrease was not statistically significant. The ratio of Bcl-2/Bax was elevated, and the levels of the cleaved forms of caspase-3 and PARP were reduced by treatment with 10-9M AHK-Cu. The present study proposed that AHK-Cu promotes the growth of human hair follicles, and this stimulatory effect may occur due to stimulation of the proliferation and the preclusion of the apoptosis of DPCs. [ABSTRACT FROM AUTHOR]

Pathogenetic mechanisms in androgenetic alopecia are not yet fully understood; however, it is commonly accepted that androgens like testosterone (T) and 5α-dihydrotestosterone (5α-DHT) inhibit hair follicle activity with early induction of the catagen. Thus, we investigated the influence of T and 5α-DHT on proliferation, cell death and bcl-2/bax expression in cultured dermal papilla cells (DPC) from nonbalding scalp regions of healthy volunteers. T and 5α-DHT induced apoptosis in DPC in a dose-dependent and time-related manner; in addition a necrotic effect due to T at 10-5M was found. Interestingly, bcl-2 protein expression was decreased in T- and 5α-DHT-treated cells, leading to an increase in the bax/bcl-2 ratio. In addition, T and 5α-DHT induced proteolytic cleavage of caspase 8 and inhibited proliferation of DPC at 10-5M. High concentrations of T and 5α-DHT were needed to induce apoptotic effects in DPC. These data suggest that DPC from nonbalding scalp regions do have the capacity to undergo apoptosis, but need a high androgen stimulus. The present study provides an interesting new pathogenetic approach in androgenetic alopecia. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Dermal papilla cells (DPC) control the growth character of the hair follicle through their elaboration of mitogenic factors and extracellular matrix components. Further, the dermal papilla is a primary site of androgen action in the hair follicle. Interleukin-1 α (IL-1 α) is prominent in skin wounding and inflammatory responses although regarded as a negative hair growth regulator. We studied the effect of IL-1 α and the potent androgen 5 α-dihydrotestosterone (DHT) on the expression of the androgen receptor (AR) and various factors secreted by cultured human temporal scalp DPC. IL-1 α triggered cellular changes consistent with nuclear factor- κB pathway activation as well as reduced AR mRNA and protein expression levels for DHT-stimulated DPC. This cytokine also increased DPC supernatant keratinocyte growth factor (KGF), vascular endothelial growth factor (VEGF), IL-8 and granulocyte-macrophage colony-stimulating factor (GM-CSF) concentrations. IL-1 α did not influence DPC supernatant levels of transforming growth factor- β1, a negative hair growth regulator. The stimulatory effect of IL-1 α on DPC VEGF, GM-CSF, KGF, and IL-8 expression was also evident at the mRNA level for these cytokines. IL-1 α also increased mRNA transcript levels of protease-nexin-1, a secreted serine protease inhibitor expressed in the dermal papilla of anagen-stage hair follicles. Although DHT did not affect supernatant cytokine concentrations, the androgen altered mRNA transcript levels of several factors for DPC co-stimulated with IL-1 α. In consideration of its in vitro activity profile, IL-1 α may be an important modifier of dermal papilla activity as well as potentially influence androgen-regulated gene expression in DPC. [ABSTRACT FROM AUTHOR]

The dermal papilla is a cluster of specialised mesenchymal cells at the bottom of the mammalian hair follicle, embedded in a loose extracellular matrix. These cells have the capability to induce and support hair growth via close epithelial–mesenchymal interactions with the keratinocytes surrounding the hair matrix. The extracellular matrix of the dermal papilla differs markedly from the interfollicular matrix and plays a key role in the maintenance of hair growth. In this study we investigated the expression pattern and activity of matrix metalloproteinases (MMP) and their tissue inhibitor in in vitro cultures of cells derived from scalp dermal papilla and fibrous sheath. Expression and activity of MMP-1, MMP-2, MMP-3, MMP-9, TIMP-1, TIMP-2 and MT1-MMP were analysed in those cells cultured in contact with one of the relevant protein component of the dermal matrix, collagen type I as well as in monolayer. Zymographic analysis showed activation of MMP-2 in all cells grown in three-dimensional collagen lattices whereas MMP-9 was activated only in three-dimensional collagen cultures of dermal fibroblasts and weakly in follicular cells. Expression of MMP-1, TIMP-1, TIMP-2 and MT1-MMP was similar in all cells, in both culture conditions, whereas expression of MMP-3 was absent in dermal papilla cells. In addition to a series of reported morphological and functional differences between dermal fibroblasts and the dermal mesenchyme-derived cells of the hair follicle, we reported differences in MMP expression in dermal papilla and fibrous sheath cells within the mesenchymal population of the hair follicle. [ABSTRACT FROM AUTHOR]

The dermal papilla plays pivotal roles in hair follicle cycle and dermal papilla cells (DPCs) with aggregative behavior have more obviously inductive ability. In the present study, the suppression subtractive hybridization method was employed to identify the differentially expressed genes in dermal papillae cells with aggregative behavior. Following mRNA isolation of DPC with and without aggregative behavior, cDNA of both populations were prepared and subtracted by suppression PCR. Sequencing of enriched cDNAs identified five genes differentially expressed including capping protein, paladin, and vascular endothelial growth factor. Interestingly, HSPC016, first cloned from CD34+ hematopoietic stem/progenitor cells (HSPC), was identified by SSH, cDNA dot blot and Northern blot, which showed that this gene was differentially expressed in DPC with aggregative behavior. The full-length cDNA of HSPC016 was shown to be 366 bp, and the possible function of HSPC016 related to transcriptional regulation. [ABSTRACT FROM AUTHOR]

Background: Minoxidil has been widely used to treat androgenetic alopecia, but little is known about its pharmacological activity or about the identity of its target cells in hair follicles. We hypothesized that minoxidil has direct effects on the proliferation and apoptosis of dermal papilla cells (DPCs) of human hair follicle. Objective: To elucidate the mechanism of topical minoxidil action in terms of stimulating hair growth. Methods: We evaluated cell proliferations in cultured DPCs by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and measured the expressions of extracellular signal-regulated kinase (ERK), Akt, Bcl-2, and Bax by Western blot. We also measured elongation of hair follicles in organ culture. Results: Minoxidil significantly increased the proliferation of DPCs. The levels of ERK phosphorylation and of phosphorylated Akt increased significantly 1 h post-treatment; percentage increase of ERK phosphorylation was 287% at 0.1 μM and 351% at 1.0 μM of minoxidil, and that of Akt phosphorylation was 168% at 0.1 μM and 257% at 1.0 μM of minoxidil. 1.0 μM of minoxidil increased Bcl-2 expression over 150%, while 1.0 μM of minoxidil decreased Bax expression by more than 50%. Moreover, a significant elongation of individual hair follicles in organ culture was observed after adding minoxidil. Conclusion: Minoxidil promotes the survival of human DPCs by activating both ERK and Akt and by preventing cell death by increasing the ratio of Bcl-2/Bax. We suggest that minoxidil stimulates the growth of human hairs by prolonging anagen through these proliferative and anti-apoptotic effects on DPCs. [Copyright &y& Elsevier]

The metabolism of radioactive dehydroepiandrosterone (DHEA) and testosterone was studied in dermal papilla cells (DPC) and dermal fibroblasts (DFB) derived from hair follicles from two different body sites (head, flank) of four male, castrated beagle dogs. Thin layer chromatography was used for separation, and autoradiography for identification of the radioactive metabolites. DHEA was metabolized mainly to 11α-OH-testosterone and only to a minor extent to 11α-OH-androstenedione and another unidentified metabolite. The highest percentage of metabolization of DHEA was found in DFB of the head. Testosterone was metabolized only to a minor extent (less than 10%) to 5α-dihydrotestosterone and epiandrosterone and there was no significant difference between either the two cell types or the two locations. These results clearly show that the metabolization of androgens in canine DPC and DFB is different from that observed in cells from the human hair follicle. [ABSTRACT FROM AUTHOR]

Abstract: Platelet-derived growth factor (PDGF) is a potent mitogenic factor for many cell types and has been shown to be important in follicular development and vasculogenesis. In this study, we examined the expression pattern of both PDGF factors and their corresponding receptors in mesenchyme-derived dermal papilla cells (DPCs) and epithelial follicular keratinocytes (FKs). Both types of PDGF receptors are expressed in FKs, whereas DPCs only express PDGF receptor β on the protein level, a finding also seen in whole organ cultures. By examining the expression of PDGF ligands, we were able to show that cultured FKs synthesize both PDGF-A and PDGF-B, whereas, DPCs only express PDGF-A. As immunomodulatory cytokines were shown to affect hair growth, we investigated the effects of IL-1β, IL-4, TNF-α, TGF-β and IFN-γ on the expression levels of PDGF factors in cultured DPCs and FKs. Interestingly, we could show a significant down-regulatory effect by catagen-inducing cytokines like IL-1β or IFN-γ, suggesting a possible involvement of PDGF signaling in the induction of catagen. The question concerning the latter hypothesis remains to be elucidated in further studies on whole organ cultures. [ABSTRACT FROM AUTHOR]

Since the way in which the hair follicle functions is not well understood, many hair disorders are poorly controlled. A range of in vitro and in vivo models have therefore been developed to investigate the cell biological and biochemical mechanisms involved in the organization of this complex tissue. These range from cultures of a single cell type, such as those of the regulatory, mesenchyme-derived dermal papilla, through organ culture of isolated follicles to natural or genetically manipulated animal models. Each system has advantages and disadvantages for studying particular aspects of follicular function and some are potentially useful for the development of novel treatments for hair disorders. [ABSTRACT FROM AUTHOR]

Abstract Skin biopsies were taken from female dogs, the primary hair follicles isolated and the dermal papilla dissected. After incubation in supplemented Amniomax complete C100 medium in 24-well culture plates, the dermal papilla cells (DPC) grew to confluence within 3 weeks. Thereafter, they were subcultivated every 7 days. Dermal fibroblast (DFB) cultures were established by explant culture of interfollicular dermis in serum-free medium, where they reached confluence in 10 days. They were subcultivated every 5 days. For immunohistochemistry, cells were grown on cover slips for 24 h, fixed and stained with antibodies against collagen IV and laminin. DPC showed an aggregative growth pattern and formation of pseudopapillae. Intensive staining for collagen IV and laminin could be observed until the sixth passage. DFB grew as branching, parallel lines and showed only weak staining for collagen IV and laminin. [ABSTRACT FROM AUTHOR]