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An essential role for dermal primary cilia in hair follicle morphogenesis.

ABSTRACT: The primary cilium is a microtubule-based organelle implicated as an essential component of a number of signaling pathways. It is present on cells throughout the mammalian body; however, its functions in most tissues remain largely unknown. Herein we demonstrate that primary cilia are present on cells in murine skin and hair follicles throughout morphogenesis and during hair follicle cycling in postnatal life. Using the Cre-lox system, we disrupted cilia assembly in the ventral dermis and evaluated the effects on hair follicle development. Mice with disrupted dermal cilia have severe hypotrichosis (lack of hair) in affected areas. Histological analyses reveal that most follicles in the mutants arrest at stage 2 of hair development and have small or absent dermal condensates. This phenotype is reminiscent of that seen in the skin of mice lacking Shh or Gli2. In situ hybridization and quantitative RT-PCR analysis indicates that the hedgehog pathway is downregulated in the dermis of the cilia mutant hair follicles. Thus, these data establish cilia as a critical signaling component required for normal hair morphogenesis and suggest that this organelle is needed on cells in the dermis for reception of signals such as sonic hedgehog.

SUBMITTER: Lehman JM

PROVIDER: S-EPMC2677658 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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An essential role for dermal primary cilia in hair follicle morphogenesis.

Lehman Jonathan M JM Laag Essam E Michaud Edward J EJ Yoder Bradley K BK

The Journal of investigative dermatology 20081106 2

The primary cilium is a microtubule-based organelle implicated as an essential component of a number of signaling pathways. It is present on cells throughout the mammalian body; however, its functions in most tissues remain largely unknown. Herein we demonstrate that primary cilia are present on cells in murine skin and hair follicles throughout morphogenesis and during hair follicle cycling in postnatal life. Using the Cre-lox system, we disrupted cilia assembly in the ventral dermis and evalua ...[more]

PMID: 18987668

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Project description:Many active pharmaceutical ingredients (API) possess poor aqueous solubility and thus lead to poor bioavailability upon oral administration and topical application. Nanocrystals have a well-established, universal formulation approach to overcome poor solubility. Various nanocrystal-based products have entered the market for oral application. However, their use in dermal formulations is relatively novel. Previous studies confirmed that nanocrystals are a superior formulation principle to improve the dermal penetration of poorly soluble API. Other studies showed that nanocrystals can also be used to target the hair follicles where they create a drug depot, enabling long acting drug therapy with only one application. Very recent studies show that also the vehicle in which the nanocrystals are incorporated can have a tremendous influence on the pathway of the API and the nanocrystals. In order to elucidate the influence of the excipient in more detail, a systematic study was conducted to investigate the influence of excipients on the penetration efficacy of the formulated API and the pathway of nanocrystals upon dermal application. Results showed that already small quantities of excipients can strongly affect the passive dermal penetration of curcumin and the hair follicle targeting of curcumin nanocrystals. The addition of 2% ethanol promoted hair follicle targeting of nanocrystals and hampered passive diffusion into the stratum corneum of the API, whereas the addition of glycerol hampered hair follicle targeting and promoted passive diffusion. Propylene glycol was found to promote both pathways. In fact, the study proved that formulating nanocrystals to improve the bioefficacy of poorly soluble API upon dermal application is highly effective. However, this is only true, if the correct excipient is selected for the formulation of the vehicle. The study also showed that excipients can be used to allow for a targeted dermal drug delivery, which enables to control if API should be delivered via passive diffusion and/or as drug reservoir by depositing API in the hair follicles.

Project description:Hair follicle stem cells are extensively reprogrammed by the aging process, manifesting as diminished self-renewal and delayed responsiveness to activating cues, orchestrated by both intrinsic microenvironmental and extrinsic macroenvironmental regulators. Dermal white adipose tissue (dWAT) is one of the peripheral tissues directly adjacent to hair follicles (HFs) and acts as a critical macroenvironmental niche of HF. dWAT directly contributes to HF aging by paracrine signal secretion. However, the altered interrelationship between dWAT and HF with aging has not been thoroughly understood. Here, through microdissection, we separated dWAT from the skin of aged mice (18 months) and young mice (2 months) in telogen and depilation-induced anagen for transcriptome comparing. Notably, compared with young dWAT, aberrant inflammatory regulators were recapitulated in aging dWAT in telogen, including substantial overexpressed inflammatory cytokines, matrix metalloproteinases, and prostaglandin members. Nonetheless, with anagen initiation, inflammation programs were mostly abolished in aging dWAT, and instead of which, impaired collagen biosynthesis, angiogenesis, and melanin synthesis were identified. Furthermore, we confirmed the inhibitory effect on hair growth of CXCL1, one of the most significantly upregulated inflammation cytokines in aging dWAT. Besides this, we also identified the under-expressed genes related to Wnt signaling fibroblast growth factor family members and increased BMP signaling in aging dWAT, further unraveling the emerging role of dWAT in aging HFs malfunction. Finally, we proved that relieving inflammation of aging dWAT by injecting high-level veratric acid stimulated HF regenerative behavior in aged mice. Concomitantly, significantly decreased TNF-a, CCL2, IL-5, CSF2, and increased IL10 in dWAT was identified. Overall, the results elaborated on the complex physiological cycling changes of dWAT during aging, providing a basis for the potential regulatory effect of dWAT on aging HFs.

Dataset Information

An essential role for dermal primary cilia in hair follicle morphogenesis.

Publications

An essential role for dermal primary cilia in hair follicle morphogenesis.

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