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Mitotic Diversity in Homeostatic Human Interfollicular Epidermis

Department of Genetics of Skin Carcinogenesis, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
Department of RNA Biology and Cancer, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
IUF–Leibniz Research Institute for Environmental Medicine, Düsseldorf 40225, Germany
Division of Cancer Research, Department of Thoracic Surgery, Medical Center, University of Freiburg-Faculty of Medicine, University of Freiburg, Breisacher Str. 115, Freiburg 79106, Germany
German Cancer Consortium (DKTK), Freiburg 79106, Germany
Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, Heidelberg 69120, Germany
Author to whom correspondence should be addressed.
Academic Editor: Wilhelm Bloch
Int. J. Mol. Sci. 2016, 17(2), 167;
Received: 30 November 2015 / Revised: 8 January 2016 / Accepted: 15 January 2016 / Published: 28 January 2016
(This article belongs to the Special Issue Stem Cell Activation in Adult Organism)
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Despite decades of skin research, regulation of proliferation and homeostasis in human epidermis is still insufficiently understood. To address the role of mitoses in tissue regulation, we utilized human long-term skin equivalents and systematically assessed mitoses during early epidermal development and long-term epidermal regeneration. We now demonstrate four different orientations: (1) horizontal, i.e., parallel to the basement membrane (BM) and suggestive of symmetric divisions; (2) oblique with an angle of 45°–70°; or (3) perpendicular, suggestive of asymmetric division. In addition, we demonstrate a fourth substantial fraction of suprabasal mitoses, many of which are committed to differentiation (Keratin K10-positive). As verified also for normal human skin, this spatial mitotic organization is part of the regulatory program of human epidermal tissue homeostasis. As a potential marker for asymmetric division, we investigated for Numb and found that it was evenly spread in almost all undifferentiated keratinocytes, but indeed asymmetrically distributed in some mitoses and particularly frequent under differentiation-repressing low-calcium conditions. Numb deletion (stable knockdown by CRISPR/Cas9), however, did not affect proliferation, neither in a three-day follow up study by life cell imaging nor during a 14-day culture period, suggesting that Numb is not essential for the general control of keratinocyte division. View Full-Text
Keywords: human epidermis; suprabasal mitosis; Numb; asymmetric mitosis; long-term organotypic culture model; epidermal differentiation human epidermis; suprabasal mitosis; Numb; asymmetric mitosis; long-term organotypic culture model; epidermal differentiation

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Nöske, K.; Stark, H.-J.; Nevaril, L.; Berning, M.; Langbein, L.; Goyal, A.; Diederichs, S.; Boukamp, P. Mitotic Diversity in Homeostatic Human Interfollicular Epidermis. Int. J. Mol. Sci. 2016, 17, 167.

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