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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    • "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.
    Dental materials: official publication of the Academy of Dental Materials 12/2014; 31(2). DOI:10.1016/ · 3.77 Impact Factor
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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.
    PLoS ONE 06/2014; 9(6):e100279. DOI:10.1371/journal.pone.0100279 · 3.23 Impact Factor
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    • "The two salient features of stem cells are their ability to self-renew, and their ability to differentiate into specialized tissues [29,30]. An emerging model is that quiescent stem cells reside at low levels of ROS and slight increases in ROS are necessary signals for self-renewal and cellular differentiation [31-33]. ROS levels above those required for self-renewal or differentiation impair these critical two stem cell properties and result in stem cell hyper-proliferation, resulting in stem cell exhaustion [34]. "
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    ABSTRACT: Mitochondria have primarily been viewed as bioenergetic and biosynthetic organelles that autonomously co-exist within the cell. However, the past two decades have provided evidence that mitochondria function as signaling organelles, constantly communicating with the cytosol to initiate biological events under homeostatic and stress conditions. Thus, the signaling function of the mitochondria may have been selected by nature from the inception of the early eukaryote, as discussed in this essay. Copyright © 2015 Elsevier Inc. All rights reserved.
    BMC Biology 05/2014; 12(1):34. DOI:10.1186/1741-7007-12-34 · 7.98 Impact Factor
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