Stromal cells provide a crucial microenvironment for overlying epithelium. Here we investigated the expression and function of a stromal cell-specific protein, stromal cell-derived factor-1 （SDF-1）, in normal human ...Stromal cells provide a crucial microenvironment for overlying epithelium. Here we investigated the expression and function of a stromal cell-specific protein, stromal cell-derived factor-1 （SDF-1）, in normal human skin and in the tissues of diseased skin. Immunohistology and laser capture microdissection （LCM）-coupled quantitative real- time RT-PCR revealed that SDF-1 is constitutively and predominantly expressed in dermal stromal cells in nor- mal human skin in vivo. To our surprise, an extremely high level of SDF-1 transcription was observed in the dermis of normal human skin in vivo, evidenced by much higher mRNA expression level than type I collagen, the most abundant and highly expressed protein in human skin. SDF-1 was also upregulated in the tissues of many human skin disorders including psoriasis, basal cell carcinoma （BCC）, and squamous cell carcinoma （SCC）. Double immunostaining for SDF-1 and HSP47 （heat shock protein 47）, a marker of fibroblasts, revealed that fibroblasts were the major source of stroma-cell-derived SDF-1 in both normal and diseased skin. Functionally, SDF-1 activates the ERK （extracellular-signal-regulated kinases） pathway and functions as a mitogen to stimulate epidermalkeratinocyte proliferation. Both overexpression of SDF-1 in dermal fibroblasts and treatment with rhSDF-1 to the skin equivalent cultures significantly increased the number of keratinocyte layers and epidermal thickness. Con- versely, the stimulative function of SDF-1 on keratinocyte proliferation was nearly completely eliminated by inter- fering with CXCR4, a specific receptor of SDF-1, or by knock-down of SDF-1 in fibroblasts. Our data reveal that extremely high levels of SDF-1 provide a crucial microenvironment for epidermal keratinocyte proliferation in both physiologic and pathologic skin conditions.展开更多
基金National Cancer Institute of Canada(011031,015053,020352) Canadian Institutes of Health Research(PPP-79109,PP2-111527,MOP130548,201603PJT-364146-PJT-CAAA-60404)+2 种基金 国家自然科学基金(11404258) 陕西省教育厅科研计划(15JS102) 陕西省重大基础研究项目(2016ZDJC-15)
文摘Stromal cells provide a crucial microenvironment for overlying epithelium. Here we investigated the expression and function of a stromal cell-specific protein, stromal cell-derived factor-1 （SDF-1）, in normal human skin and in the tissues of diseased skin. Immunohistology and laser capture microdissection （LCM）-coupled quantitative real- time RT-PCR revealed that SDF-1 is constitutively and predominantly expressed in dermal stromal cells in nor- mal human skin in vivo. To our surprise, an extremely high level of SDF-1 transcription was observed in the dermis of normal human skin in vivo, evidenced by much higher mRNA expression level than type I collagen, the most abundant and highly expressed protein in human skin. SDF-1 was also upregulated in the tissues of many human skin disorders including psoriasis, basal cell carcinoma （BCC）, and squamous cell carcinoma （SCC）. Double immunostaining for SDF-1 and HSP47 （heat shock protein 47）, a marker of fibroblasts, revealed that fibroblasts were the major source of stroma-cell-derived SDF-1 in both normal and diseased skin. Functionally, SDF-1 activates the ERK （extracellular-signal-regulated kinases） pathway and functions as a mitogen to stimulate epidermalkeratinocyte proliferation. Both overexpression of SDF-1 in dermal fibroblasts and treatment with rhSDF-1 to the skin equivalent cultures significantly increased the number of keratinocyte layers and epidermal thickness. Con- versely, the stimulative function of SDF-1 on keratinocyte proliferation was nearly completely eliminated by inter- fering with CXCR4, a specific receptor of SDF-1, or by knock-down of SDF-1 in fibroblasts. Our data reveal that extremely high levels of SDF-1 provide a crucial microenvironment for epidermal keratinocyte proliferation in both physiologic and pathologic skin conditions.
