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Vol. 15, Issue 10, 4647-4657, October 2004
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* Department of Pathology and Biodefence, Faculty of Medicine, Saga University, Saga 849-8501, Japan;
Department of Internal Medicine, Faculty of Medicine, Saga University, Saga 849-8501, Japan
Submitted January 16, 2004;
Revised July 2, 2004;
Accepted July 21, 2004
Monitoring Editor: Carl-Henrik Heldin
Mesenchymal cell types, under mesenchymal-epithelial interaction, are involved in tissue regeneration. Here we show that bone marrow stromal cells (BMSCs), subcutaneous preadipocytes, and dermal fibroblasts distinctively caused keratinocytes to promote epidermal regeneration, using a skin reconstruction model by their coculture with keratinocytes. Three mesenchymal cell types promoted the survival, growth, and differentiation of keratinocytes, whereas BMSCs and preadipocytes inhibited their apoptosis. BMSCs and preadipocytes induced keratinocytes to reorganize rete ridge- and epidermal ridge-like structures, respectively. Keratinocytes with fibroblasts or BMSCs expressed the greatest amount of interleukin (IL)-1
protein, which is critical for mesenchymal-epithelial cross-talk in skin. Keratinocytes with or without three mesenchymal supports displayed another cross-talk molecule, c-Jun protein. Without direct mesenchymal-epithelial contact, the rete ridge- and epidermal ridge-like structures were not replicated, whereas the other phenomena noted above were. DNA microarray analysis showed that the mesenchymal-epithelial interaction affected various gene expressions of keratinocytes and mesenchymal cell types. Our results suggest that not only skin-localized fibroblasts and preadipocytes but also BMSCs accelerate epidermal regeneration in complexes and that direct contact between keratinocytes and BMSCs or preadipocytes is required for the skin-specific morphogenesis above, through mechanisms that differ from the IL-1/c-Jun pathway.
Abbreviations used: -SMA, alpha-smooth muscle actin; AP-1, activator protein 1; BMSC, bone marrow stromal cell; CK, cytokeratin; GM-CSF, granulocyte macrophage-colony stimulating factor; H&E, hematoxylin and eosin; IL, interleukin; KGF, keratinocyte growth factor; PVDF, polyvinylidene difluoride; ssDNA, single-stranded DNA.
Corresponding author. E-mail address: aokis{at}med.saga-u.ac.jp.
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