The myofibroblast matrix: implications for tissue repair and fibrosis

Myofibroblasts, and the extracellular matrix ( ECM ) in which they reside, are critical components of wound healing and fibrosis. The ECM , traditionally viewed as the structural elements within which cells reside, is actually a functional tissue whose components possess not only scaffolding characteristics, but also growth factor, mitogenic, and other bioactive properties. Although it has been suggested that tissue fibrosis simply reflects an ‘exuberant’ wound‐healing response, examination of the ECM and the roles of myofibroblasts during fibrogenesis instead suggest that the organism may be attempting to recapitulate developmental programmes designed to regenerate functional tissue. Evidence of this is provided by the temporospatial re‐emergence of embryonic ECM proteins by fibroblasts and myofibroblasts that induce cellular programmatic responses intended to produce a functional tissue. In the setting of wound healing (or physiological fibrosis), this occurs in a highly regulated and exquisitely choreographed fashion which results in cessation of haemorrhage, restoration of barrier integrity, and re‐establishment of tissue function. However, pathological tissue fibrosis, which oftentimes causes organ dysfunction and significant morbidity or mortality, likely results from dysregulation of normal wound‐healing processes or abnormalities of the process itself. This review will focus on the myofibroblast ECM and its role in both physiological and pathological fibrosis, and will discuss the potential for therapeutically targeting ECM proteins for treatment of fibrotic disorders.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94657/1/path4104.pd

The role of small leucine-rich proteoglycans in non-scarring human oral mucosal wound healing

Small leucine-rich proteoglycans (SLRPs) decorin, biglycan, fibromodulin and lumican are extracellular matrix (ECM) molecules that regulate collagen fibrilogenesis, cell functions and activity of transforming growth factor-P (TGF-ß). Thus, SLRPs may play critical roles in wound healing. In contrast to dermal wounds, gingival wounds regenerate with minimal scaring. However, the cellular and molecular mechanisms involved in this processes are not known. The aim of this study was to analyze the abundance of SLRPs, TGF-ß and Endo180, the major collagen endocytosis receptor in fibroblasts, in normal unwounded gingiva and during wound healing. The association of Endo180 with decorin was also investigated during wound healing. We hypothesized that compared to normal unwounded tissue, gingiva shows distinct localization and altered accumulation of SLRPs, TGF-ß and Endo180 during wound healing. To further analyze functions of SLRPs, we studied interaction of decorin with cultured gingival fibroblasts. Double immunostaining was used to study the localization of SLRPs, Endo180 or TGF-ß in tissue sections from normal human gingiva and up to 60 days after experimental wounding. The expression of Endo180 in cultured fibroblasts and keratinocytes was studied by immunoblotting and reverse transcriptase-polymerase chain reaction. To study interaction of cultured fibroblasts with decorin and decorin-induced signaling we used immunoblotting, function-blocking antibodies, pharmacological inhibitors, quantitative immunocytochemistry and RNA interference. In normal gingiva and during wound healing, SLRPs localized to collagen in a sitespecific manner. The immunoreactivity of SLRPs, TGF-ß1, TGF-ß3 and Endo180 was spatially and temporally regulated in myofibroblasts, pericytes, macrophages, endothelial and epithelial cells during wound healing. During wound healing, decorin colocalized with Endo180 in myofibroblasts. In cultured fibroblasts, decorin induced phosphorylation of distinct receptor tyrosine kinases leading to formation of reactive oxygen species (ROS) via the PI3K/mTOR signaling pathway. This was necessary for decorin endocytosis mainly via the clathrin-pathway. SLRPs may play a role in gingival wound re-epithelialization, collagen fibrilogenesis, ECM remodeling and cell signaling. Specifically, increased abundance of fibromodulin, decorin and TTGF-ß3 relative toTGF-ß1 may contribute to the reduced scaring during gingival wound healing. Decorin may interact with Endo180 to modulate its function and regulates cell signaling by inducing ROS formation.Dentistry, Faculty ofGraduat

Limited impact of fibromodulin deficiency on the development of experimental skin fibrosis

Excessive production of collagen is the hallmark of fatal diseases of fibrosis such as systemic sclerosis. Overexpression of the proteoglycan fibromodulin (FMOD) has been associated with improved wound healing and scarless repair. In this study we have investigated the consequences of FMOD deficiency on the development of experimental skin fibrosis. Using immunohistochemistry, we identified FMOD in both human and murine fibrotic skin. In the bleomycin model of skin fibrosis, FMOD(-/-) mice developed skin fibrosis to a similar degree compared to FMOD(+/+) mice. Analysis of skin ultrastructure using transmission electron microscopy revealed a significant reduction in collagen fibril diameter in FMOD(-/-) but not FMOD(+/+) mice following fibrosis. We conclude that impact of FMOD deficiency on the development of experimental skin fibrosis is limited. This article is protected by copyright. All rights reserved