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First published online 22 October 2003
doi: 10.1242/dev.00837

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130/24/6049    most recent
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Development 130, 6049-6063 (2003)
Copyright © 2003 The Company of Biologists Limited

Role of melanoma chondroitin sulphate proteoglycan in patterning stem cells in human interfollicular epidermis

James Legg1,*, Uffe B. Jensen2, Simon Broad1, Irene Leigh3 and Fiona M. Watt1,{ddagger}

1 Keratinocyte Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK
2 Institute of Human Genetics, The Bartholin Building, University of Aarhus, DK-8000 Aarhus C, Denmark
3 Cancer Research UK Skin Tumour Laboratory, The Royal London Hospital, 2 Newark Street, London, E1 2AT, UK

{ddagger} Author for correspondence (e-mail: fiona.watt{at}cancer.org.uk)

Accepted 28 August 2003

Human interfollicular epidermis is renewed by stem cells that are clustered in the basal layer in a patterned, non-random distribution. Stem cells can be distinguished from other keratinocytes by high expression of ß1 integrins and lack of expression of terminal differentiation markers; they divide infrequently in vivo but form actively growing colonies in culture. In a search for additional stem cell markers, we observed heterogeneous epidermal expression of melanoma chondroitin sulphate proteoglycan (MCSP). MCSP was expressed by those keratinocytes with the highest ß1 integrin levels. In interfollicular epidermis, expression was confined to non-cycling cells and, in culture, to self-renewing clones. However, fluorescence-activated cell sorting on the basis of MCSP and ß1 integrin expression gave no more enrichment for clonogenic keratinocytes than sorting for ß1 integrins alone. To interfere with endogenous MCSP, we retrovirally infected keratinocytes with a chimera of the CD8 extracellular domain and the MCSP cytoplasmic domain. CD8/MCSP did not affect keratinocyte proliferation or differentiation but the cohesiveness of keratinocytes in isolated clones or reconstituted epidermal sheets was greatly reduced. CD8/MCSP caused stem cell progeny to scatter without differentiating. CD8/MCSP did not alter keratinocyte motility but disturbed cadherin-mediated cell-cell adhesion and the cortical actin cytoskeleton, effects that could be mimicked by inhibiting Rho. We conclude that MCSP is a novel marker for epidermal stem cells that contributes to their patterned distribution by promoting stem cell clustering.

Key words: Melanoma chondroitin sulphate proteoglycan, Epidermal stem cells, Patterning


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Development 2003 130: 2404. [Full Text]  





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