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THE STEM CELL NICHE

A Stable Niche Supports Long-Term Maintenance of Human Epidermal Stem Cells in Organotypic Cultures

^aDivision of Genetics of Skin Carcinogenesis, German Cancer Research Center, Heidelberg, Germany;
^bDepartment of Internal Medicine and
^cWomen's Clinic, University Clinic of Tübingen, Tübingen, Germany;
^dDepartment of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA

Key Words. Collagen-based organotypic cultures • Scaffold-based organotypic cultures • Stem cell markers • Label-retaining cells • Stem cell niche

Correspondence: Correspondence: Petra Boukamp, Ph.D.,Division of Genetics of Skin Carcinogenesis, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. Telephone: 49-6221-424516; Fax: 49-6221-423457; e-mail: P.Boukamp{at}DKFZ-Heidelberg.de

Received on December 20, 2007; accepted for publication on July 11, 2008.

First published online in STEM CELLS EXPRESS  July 24, 2008.

Stem cells in human interfollicular epidermis are still difficult to identify, mainly because of a lack of definitive markers and the inability to label human beings for label-retaining cells (LRCs). Here, we report that LRCs could be identified and localized in organotypic cultures (OTCs) made with human cells. Labeling cultures for 2 weeks with iododeoxyuridine (IdU) and then chasing for 6–10 weeks left <1% of basal cells retaining IdU label. Whole mounts demonstrated that LRCs were individually dispersed in the epidermal basal layer. Some LRCs, but not all, colocalized with cells expressing melanoma chondroitin sulfate proteoglycan, a putative stem cell marker. Although we found LRCs in both collagen- and scaffold-based OTCs, only the scaffold-OTCs supported long-term survival and regeneration. LRCs ' short survival in collagen-OTCs was not due to loss of appropriate growth factors from fibroblasts. Instead, it was due to expression of metalloproteinases, especially matrix metalloproteinase (MMP)-2 and MMP-14, which caused collagen fragmentation, matrix degradation, and dislocation of specific basement membrane components bound to epidermal integrins. Blocking MMP activation not only abrogated MMP-dependent matrix degradation but also increased longevity of the epidermis and the LRCs in these cultures. Such findings indicate that the stem cell niche, the microenvironment surrounding and influencing the stem cell, is essential for stem cell survival and function, including long-term tissue regeneration.

Disclosure of potential conflicts of interest is found at the end of this article.