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

Abstract

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-1b (IL-1b) or tumour necrosis factor-a (TNF-a), and the transformed cells were characterized by electron microscopy, immunohistochemistry and quantitative RT-PCR. Results: After short-term exposure to IL-1b or TNF-a (<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 a-smooth muscle actin, type I collagen and calponin, and by quantitative RT-PCR gene expression of type I collagen and a-smooth muscle actin. Conclusions: Long-term exposure to TNF-a or IL-1b 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.Chaudhuri V, Zhou L, Karasek M. Inflammatory cytokines induce the transformation of human dermal microvascular endothelial cells into myofibroblasts: a potential role in skin fibrogenesis.

The Protective Effects of Bevacizumab in Bleomycin-Induced Experimental Scleroderma

“…If so, migrated local and bone marrow derived endothelial cells may transform into the different cells for instance fibroblastic cells and thus may abrogate the fibrotic process instead of neovascularization. Endothelial cells handled by oxidative stress [12] and cytokines [11] have been reported to transform into fibroblastic cells.…”

“…In addition to the autonomy of fibroblasts, transformation of the non-fibroblastic cells to fibroblastic cells is the other possible pathogenic way leading to scleroderma. Endothelial cells cultured with fibroblast growth factor [10], and exposed to tumor necrosis factor alpha (TNF-α) or IL-1β [11] are observed to transform into myofibroblastic cells. Endothelial-myofibroblastic cell transformation is also reported by the application of homocysteine, a potent oxidant [12].…”

The origin of the myofibroblast in fibroproliferative vasculopathy: Does the endothelial cell steer the pathophysiology of systemic sclerosis?

“…Recently, it has been reported with increasing frequency that vascular endothelial cells (ECs) have an ability to acquire matrix-producing myofibroblastic features, providing proof of principle for the process of endothelial-mesenchymal transition (EndoMT) (9)(10)(11). EndoMT is a process of nonmalignant cellular transdifferentiation by which ECs disaggregate, lose polarity, and undergo a change in their typical shape, becoming elongated and acquiring the ability to migrate into the surrounding tissue.…”

“…EndoMT is a process of nonmalignant cellular transdifferentiation by which ECs disaggregate, lose polarity, and undergo a change in their typical shape, becoming elongated and acquiring the ability to migrate into the surrounding tissue. It is a phenotypic conversion characterized by the loss of vascular EC markers such as CD31, von Willebrand factor, and VE-cadherin, and the emergence of mesenchymal cell markers such as ␣-SMA, vimentin, type I procollagen, and S100A4/fibroblastspecific protein 1 (9)(10)(11)(12).…”

“…Findings in experimental wound repair have suggested that EndoMT may also take place during the formation of granulation tissue (11). Others have observed that microvascular ECs differentiate into mesenchymal cells in response to chronic inflammatory stimuli (10).…”