Inflammatory cytokines induce the transformation of human dermal microvascular endothelial cells into myofibroblasts: a potential role in skin fibrogenesis

Background: The myofibroblast plays a central role in wound contraction and in the pathology of fibrosis. The origin(s) of this important cell type in skin has not been firmly established. Methods: Human epithelioid dermal microvascular endothelial cells (HDMEC) were isolated from foreskin tissue and maintained in cell culture. The transformation of epithelioid HDMEC into myofibroblasts (EMT) was induced by the inflammatory cytokines interleukin-1 beta (IL-1 beta) or tumour necrosis factor-alpha (TNF-alpha), and the transformed cells were characterized by electron microscopy, immunohistochemistry and quantitative RT-PCR. Results: After short-term exposure to IL-1 beta or TNF-alpha (< 3 days), EMT was reversible; after long-term exposure (> 10 days), EMT was permanent. The transformed cells were identified as myofibroblasts by cytoplasmic microfilaments with dense bodies and attachment plaques, by the expression of alpha-smooth muscle actin, type I collagen and calponin, and by quantitative RT-PCR gene expression of type I collagen and alpha-smooth muscle actin. Conclusions: Long-term exposure to TNF-alpha or IL-1 beta induced the permanent transformation of HDMEC into myofibroblasts in cell culture. A similar transformation following chronic inflammatory stimulation in vivo may explain one source of myofibroblasts in skin fibrogenesis.