Mitochondrial Reactive Oxygen Species Promote Epidermal Differentiation and Hair Follicle Development

1Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Science Signaling (Impact Factor: 6.28). 02/2013; 6(261):ra8. DOI: 10.1126/scisignal.2003638
Source: PubMed


Proper regulation of keratinocyte differentiation within the epidermis and follicular epithelium is essential for maintenance of epidermal barrier function and hair growth. The signaling intermediates that regulate the morphological and genetic changes associated with epidermal and follicular differentiation remain poorly understood. We tested the hypothesis that reactive oxygen species (ROS) generated by mitochondria are an important regulator of epidermal differentiation by generating mice with a keratinocyte-specific deficiency in mitochondrial transcription factor A (TFAM), which is required for the transcription of mitochondrial genes encoding electron transport chain subunits. Ablation of TFAM in keratinocytes impaired epidermal differentiation and hair follicle growth and resulted in death 2 weeks after birth. TFAM-deficient keratinocytes failed to generate mitochondria-derived ROS, a deficiency that prevented the transmission of Notch and β-catenin signals essential for epidermal differentiation and hair follicle development, respectively. In vitro keratinocyte differentiation was inhibited in the presence of antioxidants, and the decreased differentiation marker abundance in TFAM-deficient keratinocytes was partly rescued by application of exogenous hydrogen peroxide. These findings indicate that mitochondria-generated ROS are critical mediators of cellular differentiation and tissue morphogenesis.

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    • "The arguments behind this election are clear: H 2 O 2 is easily handled and produced, and it is the most relevant ROS molecule , along with Å O 2 À , physiologically produced by cells to signal[1,12]. Currently it is an established fact that there is a H 2 O 2 concentration gradient whereby moderate to high concentrations (10 À4 –10 À3 M) induce cell death, cell cycle arrest and senescence in different in vitro and in vivo models[6,17,20,45], while low concentrations (10 À7 –10 À5 M) modulate signalling pathways in order to enhance proliferation, wound healing, differentiation and tissue modelling[5,22,23,46]. In this line, Ibañez et al. had shown recently that scavenging the physiological levels of H 2 O 2 , both in vitro and in vivo, employing catalase leads to a cell cycle arrest at G 1 through increased levels of p27 KIP1 protein[47]. "
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    ABSTRACT: Photodynamic treatments allow control of the amount of reactive oxygen species (ROS) produced through the photosensitizer concentration and the light dose delivered to the target. In this way low ROS doses can be achieved in situ to study cell responses related to redox regulation. In this study a comparison has been made between different cell responses to a low-dose photodynamic treatment and both low and relatively high concentrations of H2O2 in human immortalized keratinocytes (HaCaT). The obtained results show that the photodynamic treatment induces a stimulating cell response roughly equivalent to that produced by exposing cells to 10−5 M H2O2. Higher H2O2 concentrations gave rise to concentration-dependent deleterious effects on the cell cultures. Of importance is that the photodynamic treatment did not produce genotoxic damage, as measured by micronuclei frequency, while cultures exposed to 10−5 M H2O2 displayed a significant increase in the amount of cells with micronuclei. In summary, the low-dose photodynamic treatment promotes cell proliferation but does not incur in the excessive clastogenic lesions observed after H2O2 exposure. It is therefore proposed as a promising alternative to direct H2O2 exposure in the study of cell redox signalling.
    No preview · Article · Feb 2015 · Journal of Photochemistry and Photobiology B Biology
    • "Biological events induced by metal ions have been determined to be related to an increased concentration of intracellular reactive oxygen species (ROS) because these species serve as signaling intermediates in cellular signaling pathways, including cell differentiation, proliferation and apoptosis [20] [28]. Previous studies suggested that increased intracellular ROS may play an early causal role in the terminal differentiation in keratinocytes [29] [30]. Therefore, the terminal differentiation of oral keratinocytes via increased intracellular ROS might be considered a potential biological event [31] [32]. "
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    ABSTRACT: Dental alloys containing indium (In) have been used in dental restoration for two decades; however, no study has investigated the biological effects of In ions, which may be released in the oral cavity, on human oral keratinocytes. The objective of the present study was to investigate the biological effects of In ions on human oral keratinocyte after confirming their release from a silver-palladium-gold-indium (Ag-Pd-Au-In) dental alloy. As a corrosion assay, a static immersion tests were performed by detecting the released ions in the corrosion solution from the Ag-Pd-Au-In dental alloy using inductively coupled plasma atomic emission spectroscopy. The cytotoxicity and biological effects of In ions were then studied with In compounds in three human oral keratinocyte cell lines: immortalized human oral keratinocyte (IHOK), HSC-2, and SCC-15. Higher concentrations of In and Cu ions were detected in Ag-Pd-Au-In (P<0.05) than in Ag-Pd-Au, and AgCl deposition occurred on the surface of Ag-Pd-Au-In after a 7-day corrosion test due to its low corrosion resistance. At high concentrations, In ions induced cytotoxicity; however, at low concentrations (∼0.8In(3+)mM), terminal differentiation was observed in human oral keratinocytes. Intracellular ROS was revealed to be a key component of In-induced terminal differentiation. In ions were released from dental alloys containing In, and high concentrations of In ions resulted in cytotoxicity, whereas low concentrations induced the terminal differentiation of human oral keratinocytes via increased intracellular ROS. Therefore, dental alloys containing In must be biologically evaluated for their safe use. Copyright © 2014 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.
    No preview · Article · Dec 2014 · Dental materials: official publication of the Academy of Dental Materials
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    • "The commencement of differentiation is regulated at several levels and by multiple influences, including Ca++ gradient, UV exposure, drug reactions etc. [4]–[7]. In vitro, keratinocyte differentiation can be induced by confluency, raising Ca++ levels, inhibition of JNK, Ephrins and other agents [4], [8]–[10]. "
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    ABSTRACT: Epidermis, a continuously self-renewing and differentiating organ, produces a protective stratum corneum that shields us from external chemical, physical and microbial threats. Epidermal differentiation is a multi-step process regulated by influences, some unknown, others insufficiently explored. Detachment of keratinocytes from the basement membrane is one such pro-differentiation stimulus. Here, we define the transcriptional changes during differentiation, especially those caused by detachment from the substratum. Using comprehensive transcriptional profiling, we revisited the effects of detachment as a differentiation signal to keratinocytes. We identified the genes regulated by detachment, the corresponding ontological categories and, using metaanalysis, compared the genes and categories to those regulated by other pro-differentiating stimuli. We identified 762 genes overexpressed in suspended keratinocyte, including known and novel differentiation markers, and 1427 in attached cells, including basal layer markers. Detachment induced epidermis development, cornification and desmosomal genes, but also innate immunity, proliferation inhibitors, transcription regulators and MAPKs; conversely the attached cells overexpressed cell cycle, anchoring, motility, splicing and mitochondrial genes, and both positive and negative regulators of apoptosis. Metaanalysis identified which detachment-regulated categories overlap with those induced by suprabasal location in vivo, by reaching confluency in vitro, and by inhibition of JUN kinases. Attached and in vivo basal cells shared overexpression of mitochondrial components. Interestingly, melanosome trafficking components were also overexpressed in the attached and in vivo basal keratinocytes. These results suggest that specific pro-differentiation signals induce specific features of the keratinization process, which are in vivo orchestrated into harmonious epidermal homeostasis.
    Full-text · Article · Jun 2014 · PLoS ONE
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