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Human hair follicles (HFs) constitute a unique microbiota habitat that differs substantially from the skin surface. Traditional HF sampling methods fail to eliminate skin microbiota contaminants or assess the HF microbiota incompletely, and microbiota functions in human HF physiology remain ill explored. Therefore, we used laser-capture microdissection, metagenomic shotgun sequencing, and FISH to characterize the human scalp HF microbiota in defined anatomical compartments. This revealed significant compartment-, tissue lineage-, and donor age-dependent variations in microbiota composition. Greatest abundance variations between HF compartments were observed for viruses, archaea, Staphylococcus epidermidis, Cutibacterium acnes, and Malassezia restricta, with the latter 2 being the most abundant viable HF colonizers (as tested by propidium monoazide assay) and, surprisingly, most abundant in the HF mesenchyme. Transfection of organ-cultured human scalp HFs with S. epidermidis-specific lytic bacteriophages ex vivo downregulated transcription of genes known to regulate HF growth and development, metabolism, and melanogenesis, suggesting that selected microbial products may modulate HF functions. Indeed, HF treatment with butyrate, a metabolite of S. epidermidis and other HF microbiota, delayed catagen and promoted autophagy, mitochondrial activity, and gp100 and dermcidin expression ex vivo. Thus, human HF microbiota show spatial variations in abundance and modulate the physiology of their host, which invites therapeutic targeting., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The role of reactive oxygen species (ROS) in the regulation of hair follicle (HF) cycle and skin homeostasis is poorly characterized. ROS have been traditionally linked to human disease and aging, but recent findings suggest that they can also have beneficial physiological functions in vivo in mammals. To test this hypothesis, we transiently switched on in situ ROS production in mouse skin. This process activated cell proliferation in the tissue and, interestingly, in the bulge region of the HF, a major reservoir of epidermal stem cells, promoting hair growth, as well as stimulating tissue repair after severe burn injury. We further show that these effects were associated with a transient Src kinase phosphorylation at Tyr416 and with a strong transcriptional activation of the prolactin family 2 subfamily c of growth factors. Our results point to potentially relevant modes of skin homeostasis regulation and demonstrate that a local and transient ROS production can regulate stem cell and tissue function in the whole organism. [ABSTRACT FROM AUTHOR]

We quantified the mRNA expression of all 22 fibroblast growth factor family members (FGF) and their four receptors (FGFR) in adult mouse full-thickness skin at various stages of the hair growth cycle. We found that in addition to mRNA encoding FGF previously identified in skin (FGF1, 2, 5, 7, 10, 13, and 22), FGF18 mRNA was also strongly expressed. Expression of these FGF varied throughout hair growth cycle: mRNA expression of FGF18 and 13 peaked at telogen; FGF7 and 10 at anagen V; and FGF5 and 22 at anagen VI.In situhybridization revealed that FGF18 mRNA is mainly expressed in the anagen inner root sheath and telogen bulge of hair follicles. In culture, FGF18 stimulated DNA synthesis in human dermal fibroblasts, dermal papilla cells, epidermal keratinocytes and vascular endothelial cells. When FGF18 was administered subcutaneously to mice in a uniform telogen state, anagen hair growth was observed. Our findings suggest that FGF18 is important for the regulation of hair growth and the maintenance of skin in adult mice. [ABSTRACT FROM AUTHOR]

Alopecia areata is an autoimmune disease targeted at hair follicles with infiltrated T lymphocytes probably playing an important role in the pathogenesis. It was reported in 1985 that mechlorethamine was effective on alopecia areata patients. This has never been confirmed since. The aims of the study were to investigate the effects of mechlorethamine on balding C3H/HeJ mice affected with an alopecia-areata-like disease and to study the underlying mechanisms. Mice were treated on half of the dorsal skin with mechlorethamine and the contralateral side was treated with the vehicle ointment. After 10 wk of mechlorethamine therapy, a full pelage of hair covered the treated side in all the mice and was maintained during the study, whereas the vehicle-treated sides showed either no change or continued hair loss. Immunohistochemistry revealed that infiltrated CD4+ and CD8+ lymphocytes were eliminated from the treated side. In vitro cell viability assay showed that lymphocytes were much more sensitive to the cytotoxic effects of mechlorethamine than skin and hair follicular cells. RNase protection assay and real-time reverse transcription polymerase chain reaction showed that tumor necrosis factor α/β, interleukin-12, and interferon-γ were inhibited by mechlorethamine upon successful treatment. Our findings support that mechlorethamine restores follicular activity by selectively targeting infiltrated lymphocytes in vivo in alopecia-areata-affected mice. [ABSTRACT FROM AUTHOR]

Cyclosporin A is an immunosuppressive agent known to cause hirsutism. The mechanisms of action that cause hirsutism have not been fully elucidated, however. We have previously reported that several selective protein kinase C inhibitors promote the growth of murine hair epithelial cells and stimulate anagen induction. In this paper, we report on an investigation of the mechanisms of action of hair-growing activity possessed by cyclosporin A from the viewpoint of whether it promotes hair epithelial cell growth or whether it modulates the expression or translocation of protein kinase C isozymes in hair epithelial cells. Our results indicate that cyclosporin A (over a wide dosage range of 1–1000 ng per ml) stimulates cultured murine hair epithelial cell growth to about 150%-160% relative to controls. We also observed growth-promoting effects on murine epidermal keratinocytes (about 140%) at the dose range of 1–100 ng per ml. At high dose ranges above 3 µg per ml, the growth of both cells was inhibited. On the other hand, we found that cyclosporin A reduces the overall expression of protein kinase C α, βI, and βII in cultured murine hair epithelial cells, and reduces the levels of protein kinase C α, βI, βII, and η in the particulate fraction from cultured murine hair epithelial cells. From these results, we speculate that the hair-growing activity of cyclosporin A is at least partially attributable to its growth-promoting influence on hair epithelial cells sequential to its downregulation of some protein kinase C isozymes in hair epithelial cells or inhibition of translocation of some protein kinase C isozymes to the membrane or cytoskeleton of hair epithelial cells. [ABSTRACT FROM AUTHOR]

We have previously reported that proanthocyanidins extracted from grape seeds possess growth-promoting activity toward murine hair epithelial cells in vitro and stimulate anagen induction in hair cycle progression in vivo. This report constitutes a comparison of the growth-promoting activity of procyanidin oligomers and the target cells of procyanidins in the skin. Results show that procyanidin dimer and trimer exhibit higher growth-promoting activity than the monomer. The maximum growth-promoting activity for hair epithelial cells with procyanidin B-2, an epicatechin dimer, reached about 300% (30 μM) relative to controls (=100%) in a 5 d culture. Optimum concentration of procyanidin C-1, an epicatechin trimer, was lower than that of procyanidin B-2; the maximum growth-promoting activity of procyanidin C-1 was about 220% (3 μM). No other flavonoid compounds examined exhibit higher proliferative activities than the procyanidins. In skin constituent cells, only epithelial cells such as hair keratinocytes or epidermal keratinocytes respond to procyanidin oligomers. Topical application of 1% procyanidin oligomers on shaven C3H mice in the telogen phase led to significant hair regeneration [procyanidin B-2, 69.6% ± 21.8% (mean ± SD); procyanidin B-3, 80.9% ± 13.0%; procyanidin C-1, 78.3% ± 7.6%] on the basis of the shaven area; application of vehicle only led to regeneration of 41.7% (SD = 16.3%). In this paper, we demonstrate the hair-growing activity of procyanidin oligomers both in vitro and in vivo, and their potential for use as agents to induce hair growth. [ABSTRACT FROM AUTHOR]

Data from the literature indicate that nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, naproxen, piroxicam, or ibuprofen, induce hair loss in vivo. These NSAIDs are well-known inhibitors of both the cytoprotective isoform of prostaglandin endoperoxide synthase-1 (PGHS-1) and of the inducible form (PGHS-2). By immunohistochemical staining, we found that PGHS-1 is the main isoform present in the dermal papilla from normal human hair follicle (either anagen or catagen), whereas PGHS-2 was only faintly and exclusively expressed in anagen dermal papilla. Thus, PGHS-1 might be the primary target of the hair growth-inhibitory effects of NSAIDS. We thus speculated that activation of PGHS-1 might be a mechanism by which minoxidil (2,4-diamino-6-piperidinopyrimidine-3-oxyde) stimulates hair growth in vivo. We demonstrate here that minoxidil is a potent activator of purified PGHS-1 (AC50 = 80 μM), as assayed by oxygen consumption and PGE2 production. This activation was also evidenced by increased PGE2 production by BALB/c 3T3 fibroblasts and by human dermal papilla fibroblasts in culture. Our findings suggest that minoxidil and its derivatives may have a cytoprotective activity in vivo and that more potent second-generation hair growth-promoting drugs might be designed, based on this mechanism. [ABSTRACT FROM AUTHOR]

Most cases of hair loss are based on premature induction of follicle regression (catagen). Deciphering the unknown regulation of catagen is therefore clinically important, but catagen is also an excellent model for organ involution by rapid terminal differentiation and for epithelial cell death (apoptosis). We here report an assay for the controlled pharmacologic induction and manipulation of catagen follicles. Dexamethasone-21-acetate (0.1%) was applied once daily to depilation-induced, growing follicles (anagen VI) on the backs of C57 B1-6 mice. Characteristic catagen-associated changes in skin color were photodocumented and assessed by morphometric histology. Topical dexamethasone induced catagen-like follicles significantly earlier, more homogeneously, and also more extensively than vehicle. This process was inhibited by high intraperitoneal doses of cyclosporin A. In addition to its clinical relevance as a screening assay for catagen-blocking drugs, this simple murine model is an attractive tool for dissecting the molecular, cellular, and developmental biology of catagen. [ABSTRACT FROM AUTHOR]

In the adult hair follicle the dermal papilla plays a crucial role in the dermal-epidermal interactions that control hair production and events of the growth cycle. It has previously been shown that cultured cells from rat vibrissa follicle dermal papillae can stimulate hair growth when implanted into amputated follicles. This study investigated the effects of implanting low-passage cultured papilla cells into small incisional wounds in the rat ear pinna. The groups of fibers that emerged from wound sites were much larger than local hairs, and often had vibrissa-type characteristics. Later-passage papilla cells or cultured skin fibroblasts failed to elicit the same response. Histology revealed that big follicles were formed when papilla cells were trapped between the cut edges of the epidermis. Abnormally large follicles were seen at wound sites many months post-operatively. Independent of epidermal influence, cultured papilla cells in the wound dermis formed rounded papilla-like aggregates that also persisted until biopsy. A previously described method of wrapping papilla cells in glabrous epidermis was less successful in percentage terms but resulted in the production of one very large vibrissa-type follicle and fiber. These results further illustrate that the inductive powers and developmental information retained by cultured derma! papilla cells parallel the properties of their embryonic precursors; the findings may have implications for human hair growth. [ABSTRACT FROM AUTHOR]