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Eur J Cell Biol. 2017 Sep;96(6):632-641. doi: 10.1016/j.ejcb.2017.03.011. Epub 2017 Apr 2.

Characterisation of cell cycle arrest and terminal differentiation in a maximally proliferative human epithelial tissue: Lessons from the human hair follicle matrix.

Author information

1
Centre for Dermatology Research, School of Biological Sciences, University of Manchester, MAHSC and NIHR Biomedical Research Centre, Manchester, UK.
2
Centre for Dermatology Research, School of Biological Sciences, University of Manchester, MAHSC and NIHR Biomedical Research Centre, Manchester, UK; MSc Toxicology Programme, University of Potsdam, Potsdam, Germany.
3
Centre for Dermatology Research, School of Biological Sciences, University of Manchester, MAHSC and NIHR Biomedical Research Centre, Manchester, UK; BSc Biosciences Programme, University of Huddersfield, Huddersfield, UK.
4
Crown Clinic, Manchester, UK.
5
Dept of Pathology, University General Hospital & Murcia University, Murcia, Spain.
6
Cell Cycle, Stem Cell Fate and Cancer Lab, Institute of Research Marqués de Valdecilla (IDIVAL), Santander, Spain.
7
Centre for Dermatology Research, School of Biological Sciences, University of Manchester, MAHSC and NIHR Biomedical Research Centre, Manchester, UK. Electronic address: ralf.paus@manchester.ac.uk.

Abstract

Human hair follicle (HF) growth and hair shaft formation require terminal differentiation-associated cell cycle arrest of highly proliferative matrix keratinocytes. However, the regulation of this complex event remains unknown. CIP/KIP family member proteins (p21CIP1, p27KIP1 and p57KIP2) regulate cell cycle progression/arrest, endoreplication, differentiation and apoptosis. Since they have not yet been adequately characterized in the human HF, we asked whether and where CIP/KIP proteins localise in the human hair matrix and pre-cortex in relation to cell cycle activity and HF-specific epithelial cell differentiation that is marked by keratin 85 (K85) protein expression. K85 expression coincided with loss or reduction in cell cycle activity markers, including in situ DNA synthesis (EdU incorporation), Ki-67, phospho-histone H3 and cyclins A and B1, affirming a post-mitotic state of pre-cortical HF keratinocytes. Expression of CIP/KIP proteins was found abundantly within the proliferative hair matrix, concomitant with a role in cell cycle checkpoint control. p21CIP1, p27KIP1 and cyclin E persisted within post-mitotic keratinocytes of the pre-cortex, whereas p57KIP2 protein decreased but became nuclear. These data imply a supportive role for CIP/KIP proteins in maintaining proliferative arrest, differentiation and anti-apoptotic pathways, promoting continuous hair bulb growth and hair shaft formation in anagen VI. Moreover, post-mitotic hair matrix regions contained cells with enlarged nuclei, and DNA in situ hybridisation showed cells that were >2N in the pre-cortex. This suggests that CIP/KIP proteins might counterbalance cyclin E to control further rounds of DNA replication in a cell population that has a propensity to become tetraploid. These data shed new light on the in situ-biography of human hair matrix keratinocytes on their path of active cell cycling, arrest and terminal differentiation, and showcase the human HF as an excellent, clinically relevant model system for cell cycle physiology research of human epithelial cells within their natural tissue habitat.

KEYWORDS:

CIP/KIP; Cell cycle arrest; Differentiation; Hair matrix; Human hair follicle; Proliferation

PMID:
28413121
DOI:
10.1016/j.ejcb.2017.03.011
[Indexed for MEDLINE]

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