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TISSUE-SPECIFIC STEM CELLS

Stem Cell Activity of Human Side Population and 6 Integrin-Bright Keratinocytes Defined by a Quantitative In Vivo Assay

^aDermatology Branch and
^bExperimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

Key Words. Xenotransplantation • Tissue engineering • MHC class I genes • Flow cytometry • Nude mice

Correspondence: Jonathan Vogel, M.D., Senior Investigator, Dermatology Branch, National Cancer Institute, NIH, Bldg. 10/Room 12N260, 10 Center Drive MSC 1908, Bethesda, Maryland 20892-1908, USA. Telephone: 301-496-9002; Fax: 301-496-5370; e-mail: jonvogel{at}mail.nih.gov

Received July 17, 2006; accepted for publication November 17, 2006.
First published online in STEM CELLS EXPRESS   November 30, 2006.



The isolation and characterization of living human epithelial stem cells is difficult because distinguishing cell surface markers have not been identified with certainty. Side population keratinocytes (SP-KCs) that efflux Hoechst 33342 fluorescent dye, analogous to bone marrow-derived side population (SP) hematopoietic stem cells, have been identified in human skin, but their potential to function as keratinocyte stem cells (KSCs) in vivo is not known. On the other hand, human keratinocyte populations that express elevated levels of β1 and 6 integrins and are distinct from SP-KCs, which express low levels of integrins, may be enriched for KSCs based on reported results of in vitro cell culture assays. When in vitro assays were used to measure total cell output of human SP-KCs and integrin-bright keratinocytes, we could not document their superior long-term proliferative activity versus unfractionated keratinocytes. To further assess the KSC characteristics in SP-KCs and integrin-bright keratinocytes, we used an in vivo competitive repopulation assay in which bioengineered human epidermis containing competing keratinocyte populations with different human major histocompatibility (MHC) class I antigens were grafted onto immunocompromised mice, and the intrinsic MHC class I antigens are used to quantify expansion of competing populations. In these in vivo studies, human SP-KCs showed little competitive expansion in vivo and were not enriched for KSCs. In contrast, keratinocytes expressing elevated levels of 6 integrin and low levels of CD71 (6-bright/CD71-dim) expanded over 200-fold during the 33-week in vivo study. These results definitively demonstrate that human 6-bright/CD71-dim keratinocytes are enriched with KSCs, whereas SP-KCs are not.

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