Activation of the Notch pathway in the hair cortex leads to aberrant differentiation of the adjacent hair-shaft layers

Little is known about the mechanisms underlying the generation of various cell types in the hair follicle. To investigate the role of the Notch pathway in this process, transgenic mice were generated in which an active form of Notch1 (Notch(DeltaE)) was overexpressed under the control of the mouse hair keratin A1 (MHKA1) promoter. MHKA-Notch(DeltaE) is expressed only in one precursor cell type of the hair follicle, the cortex. Transgenic mice could be easily identified by the phenotypes of curly whiskers and wavy, sheen pelage hair. No effects of activated Notch on proliferation were detected in hair follicles of the transgenic mice. We find that activating Notch signaling in the cortex caused abnormal differentiation of the medulla and the cuticle, two neighboring cell types that did not express activated Notch. We demonstrate that these non-autonomous effects are likely caused by cell-cell interactions between keratinocytes within the hair follicle and that Notch may function in such interactions either by directing the differentiation of follicular cells or assisting cells in interpreting a gradient emanating from the dermal papilla.

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Mouse notch: expression in hair follicles correlates with cell fate determination.

The Journal of Cell Biology ◽

10.1083/jcb.121.3.631 ◽

1993 ◽

Vol 121 (3) ◽

pp. 631-641 ◽

Cited By ~ 97

Author(s):

R Kopan ◽

H Weintraub

Keyword(s):

Hair Follicle ◽

Cell Fate ◽

Dermal Papilla ◽

Cell Types ◽

Cell Interaction ◽

Hair Follicles ◽

Skin Development ◽

High Level ◽

Cell Cell

Many vertebrate tissues, including skin, are known to develop as a consequence of epithelial-mesenchymal interactions. Much less is known about the role of cell-cell interaction within the epithelial or the mesenchymal compartments in morphogenesis. To investigate cell-cell interactions during skin development, and the potential role of the Notch homolog in this process, we cloned the mouse homolog of Notch (mNotch) and studied its expression pattern, starting as early as mesoderm formation. The novel application of double-labeled in situ hybridization in vertebrates allowed high resolution analysis to follow the fate of mNotch expressing cells directly. In comparison with the distribution of Id mRNA, analysis confirmed that in the hair follicle high levels of mNotch are expressed exclusively in the epithelial compartment. Hair follicle matrix cells start expressing mNotch as different cell types become distinguishable in the developing follicle. mNotch mRNA expression persists throughout the growth phase of the follicle and maintains the same expression profile in the second hair cycle. The cells in the follicle that undergo a phase of high level mNotch expression are in transition from mitotic precursors to several discreet, differentiating cell types. Our observations point out that both in time (during development) and in space (by being removed one cell layer from the dermal papilla) mNotch expression is clearly separated from the inductive interactions. This is a novel finding and suggests that mNotch is important for follicular differentiation and possibly cell fate selection within the follicle.

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Transglutaminase 3: The Involvement in Epithelial Differentiation and Cancer

Cells ◽

10.3390/cells9091996 ◽

2020 ◽

Vol 9 (9) ◽

pp. 1996 ◽

Cited By ~ 1

Author(s):

Elina S. Chermnykh ◽

Elena V. Alpeeva ◽

Ekaterina A. Vorotelyak

Keyword(s):

Hair Follicle ◽

Human Tumor ◽

Hair Shaft ◽

Hair Follicles ◽

Epidermal Keratinocytes ◽

Macromolecular Complexes ◽

Tumor Pathology ◽

Keratin Intermediate Filaments ◽

Transglutaminase 3

Transglutaminases (TGMs) contribute to the formation of rigid, insoluble macromolecular complexes, which are essential for the epidermis and hair follicles to perform protective and barrier functions against the environment. During differentiation, epidermal keratinocytes undergo structural alterations being transformed into cornified cells, which constitute a highly tough outermost layer of the epidermis, the stratum corneum. Similar processes occur during the hardening of the hair follicle and the hair shaft, which is provided by the enzymatic cross-linking of the structural proteins and keratin intermediate filaments. TGM3, also known as epidermal TGM, is one of the pivotal enzymes responsible for the formation of protein polymers in the epidermis and the hair follicle. Numerous studies have shown that TGM3 is extensively involved in epidermal and hair follicle physiology and pathology. However, the roles of TGM3, its substrates, and its importance for the integument system are not fully understood. Here, we summarize the main advances that have recently been achieved in TGM3 analyses in skin and hair follicle biology and also in understanding the functional role of TGM3 in human tumor pathology as well as the reliability of its prognostic clinical usage as a cancer diagnosis biomarker. This review also focuses on human and murine hair follicle abnormalities connected with TGM3 mutations.

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CD133-positive dermal papilla-derived Wnt ligands regulate postnatal hair growth

Biochemical Journal ◽

10.1042/bcj20160466 ◽

2016 ◽

Vol 473 (19) ◽

pp. 3291-3305 ◽

Cited By ~ 4

Author(s):

Linli Zhou ◽

Kun Yang ◽

April Carpenter ◽

Richard A. Lang ◽

Thomas Andl ◽

...

Keyword(s):

Hair Follicle ◽

Hair Growth ◽

Dermal Papilla ◽

Hair Shaft ◽

Hair Follicles ◽

Proliferation And Differentiation ◽

Wnt Ligands ◽

Epithelial Compartment ◽

Hair Follicle Growth

Active Wnt/β-catenin signaling in the dermal papilla (DP) is required for postnatal hair cycling. In addition, maintenance of the hair-inducing ability of DP cells in vitro requires external addition of Wnt molecules. However, whether DP cells are a critical source of Wnt ligands and induce both autocrine and paracrine signaling cascades to promote adult hair follicle growth and regeneration remains elusive. To address this question, we generated an animal model that allows inducible ablation of Wntless (Wls), a transmembrane Wnt exporter protein, in CD133-positive (CD133+) DP cells. CD133+ cells have been shown to be a specific subpopulation of cells in the DP, which possesses the hair-inducing capability. Here, we show that ablation of Wls expression in CD133+ DP cells results in a shortened period of postnatal hair growth. Mutant hair follicles were unable to enter full anagen (hair growth stage) and progressed toward a rapid regression. Notably, reduced size of the DP and decreased expression of anagen DP marker, versican, were observed in hair follicles when CD133+ DP cells lost Wls expression. Further analysis showed that Wls-deficient CD133+ DP cells led to reduced proliferation and differentiation in matrix keratinocytes and melanocytes that are needed for the generation of the hair follicle structure and a pigmented hair shaft. These findings clearly demonstrate that Wnt ligands produced by CD133+ DP cells play an important role in postnatal hair growth by maintaining the inductivity of DP cells and mediating the signaling cross-talk between the mesenchyme and the epithelial compartment.

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The Glypican-1/HGF/C-Met and Glypican-1/VEGF/VEGFR2 Ternary Complexes Regulate Hair Follicle Angiogenesis

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.781172 ◽

2021 ◽

Vol 9 ◽

Author(s):

Charlie Colin-Pierre ◽

Nicolas Berthélémy ◽

Nicolas Belloy ◽

Louis Danoux ◽

Vincent Bardey ◽

...

Keyword(s):

Hair Follicle ◽

Dermal Papilla ◽

Human Keratinocytes ◽

Hair Follicles ◽

Microvascular Endothelial Cell ◽

Outer Root Sheath ◽

Dermal Papilla Cells ◽

Root Sheath ◽

Microvascular Endothelial

The hair renewal involves changes in the morphology of the hair follicle and its micro-vascularization. In alopecia, the hair cycle is accelerated, resulting in the formation of thinner and shorter hair. In addition, alopecia is associated with a decrease in the micro-vascularization of the hair follicles. In this study, the role of glypicans (GPCs) was analyzed in the regulation of the angiogenesis of human dermal microvascular endothelial cells (HDMEC). The analysis of glypican gene expression showed that GPC1 is the major glypican expressed by human keratinocytes of outer root sheath (KORS), human hair follicle dermal papilla cells (HHFDPC) and HDMEC. KORS were demonstrated to secrete VEGF and HGF. The HDMEC pseudotube formation was induced by KORS conditioned media (KORSCM). It was totally abrogated after GPC1 siRNA transfection of HDMEC. Moreover, when cleaved by phospholipase C (PLC), GPC1 promotes the proliferation of HDMEC. Finally, GPC1 was shown to interact directly with VEGFR2 or c-Met to regulate angiogenesis induced by the activation of these receptors. Altogether, these results showed that GPC1 is a key regulator of microvascular endothelial cell angiogenesis induced by VEGF and HGF secreted by KORS. Thus, GPC1 might constitute an interesting target to tackle alopecia in dermatology research.

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The induction of hair follicle formation in the adult hooded rat by vibrissa dermal papillae

Development ◽

10.1242/dev.23.1.219 ◽

1970 ◽

Vol 23 (1) ◽

pp. 219-236

Author(s):

R. F. Oliver

Keyword(s):

Hair Follicle ◽

Hair Growth ◽

Dermal Papilla ◽

Hair Shaft ◽

Hair Follicles ◽

Hair Cycle ◽

Hair Bulb ◽

Essential Component ◽

Dermal Papillae

Hair follicles are essentially composed of two tissues. The inner epidermal component, which gives rise to, among other products, the keratinized hair shaft, is confluent with the surface epidermis and is ensheathed by the dermal component which is confluent with the pars papillaris of the dermis. A specialization of the dermal component is the dermal papilla which, in follicles producing hair, is enclosed by the epidermal matrix of the hair bulb and is connected to the dermal sheath by the papilla stalk. Many authorities have considered that the dermal papilla is an essential component of the hair follicle (reviews: Cohen, 1965; Oliver, 1969). It has been suggested that the dermal papilla may be involved in both the induction of follicle lengthening and hair growth during the proanagen phase (Chase, 1965) of the hair cycle, a concept now justified by direct experimentation in the vibrissa follicle at least (Oliver, 1967b), and perhaps also in determining the nature of the hair produced by a follicle.

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CULTURED HAIR FOLLICLE CELLS FOR THE TREATMENT OF VITILIGO

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2018.v11s3.30043 ◽

2018 ◽

Vol 11 (15) ◽

pp. 94

Author(s):

Piyatida Sutnut ◽

Saroj Suvanasuthi ◽

Kwanchanok Viravaidya-pasuwat

Keyword(s):

Human Serum ◽

Hair Follicle ◽

Cell Attachment ◽

Fetal Bovine Serum ◽

Dermal Papilla ◽

Cell Types ◽

Hair Follicles ◽

Follicle Cells ◽

Fetal Bovine ◽

Different Cell Types

Objective: The objective of this study was to develop a method to isolate cells from hair follicles and cultured them in a hydrogel.Methods: Different cell types obtained from hair follicles were investigated and mixed with three formulations of Lutrol® F-127-based hydrogels. The percentages of the cell attachment and viability were observed within 48 h.Results: The results showed that three cell types, including keratinocyte, dermal papilla, and melanocyte cells, were obtained, as shown by the expression of their corresponding genes. All formulations of the hydrogels supported cell attachment and viability. Interestingly, more than 60% cell attachment and viability were found in lutrol hydrogels supplemented with either fetal bovine serum (FBS) or heat-activated human serum.Conclusion: Higher cell attachment and viability were observed when the hair follicle cells were cultured in the hydrogel with FBS than the hydrogel with human serum. However, the lutrol gel formulation with human serum was more appropriate to be used in the future clinical study, as this formulation contained no animal-derived component.

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Localisation and regulation of cholesterol transporters in the human hair follicle: mapping changes across the hair cycle

Histochemistry and Cell Biology ◽

10.1007/s00418-020-01957-8 ◽

2021 ◽

Author(s):

Megan A. Palmer ◽

Eleanor Smart ◽

Iain S. Haslam

Keyword(s):

Hair Follicle ◽

Human Hair ◽

Vital Role ◽

Transport Proteins ◽

Hair Follicles ◽

Regulatory Control ◽

Cholesterol Transport ◽

Hair Cycle ◽

Human Hair Follicle

AbstractCholesterol has long been suspected of influencing hair biology, with dysregulated homeostasis implicated in several disorders of hair growth and cycling. Cholesterol transport proteins play a vital role in the control of cellular cholesterol levels and compartmentalisation. This research aimed to determine the cellular localisation, transport capability and regulatory control of cholesterol transport proteins across the hair cycle. Immunofluorescence microscopy in human hair follicle sections revealed differential expression of ATP-binding cassette (ABC) transporters across the hair cycle. Cholesterol transporter expression (ABCA1, ABCG1, ABCA5 and SCARB1) reduced as hair follicles transitioned from growth to regression. Staining for free cholesterol (filipin) revealed prominent cholesterol striations within the basement membrane of the hair bulb. Liver X receptor agonism demonstrated active regulation of ABCA1 and ABCG1, but not ABCA5 or SCARB1 in human hair follicles and primary keratinocytes. These results demonstrate the capacity of human hair follicles for cholesterol transport and trafficking. Future studies examining the role of cholesterol transport across the hair cycle may shed light on the role of lipid homeostasis in human hair disorders.

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Smooth muscle alpha-actin is a marker for hair follicle dermis in vivo and in vitro

Journal of Cell Science ◽

10.1242/jcs.99.3.627 ◽

1991 ◽

Vol 99 (3) ◽

pp. 627-636 ◽

Cited By ~ 2

Author(s):

C.A. Jahoda ◽

A.J. Reynolds ◽

C. Chaponnier ◽

J.C. Forester ◽

G. Gabbiani

Keyword(s):

Smooth Muscle ◽

Hair Follicle ◽

Dermal Papilla ◽

Hair Follicles ◽

Dermal Papilla Cells ◽

Smooth Muscle Alpha Actin ◽

Actin Expression ◽

Alpha Actin ◽

Sheath Cells

We have examined the expression of smooth muscle alpha-actin in hair follicles in situ, and in hair follicle dermal cells in culture by means of immunohistochemistry. Smooth muscle alpha-actin was present in the dermal sheath component of rat vibrissa, rat pelage and human follicles. Dermal papilla cells within all types of follicles did not express the antigen. However, in culture a large percentage of both hair dermal papilla and dermal sheath cells were stained by this antibody. The same cells were negative when tested with an antibody to desmin. Overall, explant-derived skin fibroblasts had relatively low numbers of positively marked cells, but those from skin regions of high hair-follicle density displayed more smooth muscle alpha-actin expression than fibroblasts from areas with fewer follicles. 2-D SDS-PAGE confirmed that, unlike fibroblasts, cultured papilla cells contained significant quantities of the alpha-actin isoform. The rapid switching on of smooth muscle alpha-actin expression by dermal papilla cells in early culture, contrasts with the behaviour of smooth muscle cells in vitro, and has implications for control of expression of the antigen in normal adult systems. The very high percentage of positively marked cultured papilla and sheath cells also provides a novel marker of cells from follicle dermis, and reinforces the idea that they represent a specialized cell population, contributing to the heterogeneity of fibroblast cell types in the skin dermis, and possibly acting as a source of myofibroblasts during wound healing.

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Abstract P050: Novel Mechanism of Ser-496 ERK5 Phosphorylation and Association with p90RSK Is Critical for Regulating C Terminus of Hsc70-Interacting Protein (CHIP) Ubiquitin E3 Ligase Activity in Diabetes-Mediated Exacerbation of Cardiomyocyte Apoptosis and Left Ventricular Dysfunction After Myocardial Infarction

Circulation Research ◽

10.1161/res.109.suppl_1.ap050 ◽

2011 ◽

Vol 109 (suppl_1) ◽

Author(s):

Nhat-Tu Le ◽

Yuichiro Takei ◽

Chang-Hoon Woo ◽

Tetsuro Shishido ◽

Yan Lu ◽

...

Keyword(s):

Transgenic Mice ◽

Cardiac Dysfunction ◽

Critical Role ◽

Active Form ◽

E3 Ligase ◽

Left Ventricular ◽

Ang Ii ◽

Lv Dysfunction ◽

On Chip

Rationale: Cardiac dysfunction is accelerated in DM patients after MI. Previously, we reported the critical role of ERK5 and CHIP association on CHIP Ub E3 ligase activity, which inhibits inducible cAMP early repressor (ICER)-mediated apoptosis and left ventricle (LV) dysfunction after MI in DM (DM + MI). Yet the regulatory mechanism of ERK5-CHIP has not been established. Objective: Since we found that p90RSK activation was increased in DM heart, we investigated whether p90RSK activation may inhibit ERK5-mediated CHIP activation, and subsequent ICER induction and apoptosis. Methods and Results: The inhibition of p90RSK activation prevented the reduction of ERK5-CHIP binding, CHIP activity, as well as ICER induction and cardiac apoptosis both in vitro after angiotensin II (ang II) stimulation and in vivo after DM + MI. p90RSK and CHIP share a same binding site with ERK5 C-terminal domain (aa571–807), and overexpression of both p90RSK and ERK5 (aa571–807) fragment, but not kinase dead mutant of p90RSK, inhibited ERK5-CHIP association, suggesting the critical role of p90RSK activation on ERK5-CHIP interaction, and competitive nature of p90RSK and CHIP against ERK5 association. Furthermore. LC-MS/MS analysis identified ERK5-S496 as being directly phosphorylated by p90RSK, and ERK5 S496A mutant significantly impaired ang II-mediated inhibition of CHIP Ub ligase activity, suggesting the critical role of Ser-496 phoaphorylation of ERK5 on CHIP activity. Therefore, p90RSK activation is critical for both p90RSK-ERK5 association as well as ERK5-Ser496 phosphorylation, and following disruption of ERK5-CHIP interaction and subsequent inhibition of CHIP Ub ligase activity. The reduction of CHIP Ub ligase activity and LV dysfunction were accelerated both in cardio-specific ERK5 knock out and wild type p90RSK transgenic mice (WT-p90RSK-Tg). Furthermore, double transgenic mice of WT-p90RSK and constitutively active form of MEK5α (specific ERK5 activator) inhibited single WT-p90RSK-Tg-medaited reduction of CHIP Ub ligase activity, LV dysfunction, and improved mortality after MI. Conclusions: These data strongly suggested that p90RSK activation accelerated cardiac dysfunction and apoptosis after DM + MI via inhibiting ERK5-CHIP module.

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