Does transformation of microvascular endothelial cells into myofibroblasts play a key role in the etiology and pathology of fibrotic disease?
Fibrosis is a major cause of human death and disability. It has been hypothesized widely that activation of resident tissue fibroblasts is responsible for the increase in matrix protein synthesis present in fibrotic tissue. More recent studies in vitro of the physiology of human dermal microvascular endothelial cells and their transformation into spindle-shaped cells by proinflammatory cytokines may provide a new explanation for the increase in myofibroblasts in fibrotic diseases. In cell culture human dermal microvascular endothelial cells transform reversibly into 2 distinct cell phenotypes observed in the endothelium in vivo: an epithelioid phenotype present in a homeostatic microvasculature and a more spindle-shaped phenotype present in an inflammed and a reactive microvasculature. When epithelioid endothelial cell cultures are exposed to proinflammatory cytokines typically increased in fibrosis in vivo (e.g. TNF-alpha and IL-beta) for sustained periods, epithelioid dermal microvascular endothelial cells transform into a spindle-shaped morphology. Many of the transformed cells are identified as myofibroblast-like cells by electron microscopy (cytoplasmic microfilaments with attachment plaques), matrix protein synthesis (type I collagen, alpha smooth muscle actin, calponin) and by RT-PCR analysis of matrix protein mRNA. Following injury to an endothelial cell culture a similar (but reversible) transformation into myofibroblast-like cells also is induced. Drugs known to slow the clinical progression to fibrosis in vivo (e.g. phosphodiesterase inhibitors, antibodies to inflammatory cytokines) are the the same drug types capable of inhibiting endothelial cell tranformation in vitro. The in vivo and in vitro observations made on blood vessel physiology and pathology following sustained inflammation support a hypothesis that endothelial cell transformation into myofibroblast-like cells may begin to explain the increase in matrix proteins and myofibroblasts pathognomonic of fibrotic disease. The experimental and clinical evidence leading to and supporting this hypothesis is presented and discussed in this report.
Karasek
Marvin Arthur
MA
Stanford University, Dermatology, 269 Campus Dr, CCSR Bldg, Rm 2115, Stanford, CA 94305, United States. marvek@stanford.edu
D002454:Cell Differentiation; D004730:Endothelium, Vascular / Q000166:cytology* / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology / Q000473:pathology / Q000502:physiology*; D005355:Fibrosis / Q000209:etiology* / Q000473:pathology; D006801:Humans; D007627:Keloid / Q000473:pathology; D008833:Microcirculation / Q000502:physiology*; D008955:Models, Cardiovascular; D032342:Muscle Cells / Q000166:cytology / Q000473:pathology / Q000502:physiology*; D012595:Scleroderma, Systemic / Q000473:pathology