TY - JOUR
T1 - Characterisation of cell cycle arrest and terminal differentiation in a maximally proliferative human epithelial tissue
T2 - Lessons from the human hair follicle matrix
AU - Purba, Talveen S.
AU - Brunken, Lars
AU - Peake, Michael
AU - Shahmalak, Asim
AU - Chaves, Asuncion
AU - Poblet, Enrique
AU - Ceballos, Laura
AU - Gandarillas, Alberto
AU - Paus, Ralf
N1 - Publisher Copyright:
© 2017
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2017/9
Y1 - 2017/9
N2 - 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.
AB - 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.
KW - CIP/KIP
KW - Cell cycle arrest
KW - Differentiation
KW - Hair matrix
KW - Human hair follicle
KW - Proliferation
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U2 - 10.1016/j.ejcb.2017.03.011
DO - 10.1016/j.ejcb.2017.03.011
M3 - Article
C2 - 28413121
AN - SCOPUS:85017437226
VL - 96
SP - 632
EP - 641
JO - European Journal of Cell Biology
JF - European Journal of Cell Biology
SN - 0171-9335
IS - 6
ER -