Scleroderma Tissue Research Articles

Capillary Regeneration in Scleroderma: Stem Cell Therapy Reverses Phenotype?

BackgroundScleroderma is an autoimmune disease with a characteristic vascular pathology. The vasculopathy associated with scleroderma is one of the major contributors to the clinical manifestations of the disease.Methodology/Principal FindingsWe used immunohistochemical and mRNA in situ hybridization techniques to characterize this vasculopathy and showed with morphometry that scleroderma has true capillary rarefaction. We compared skin biopsies from 23 scleroderma patients and 24 normal controls and 7 scleroderma patients who had undergone high dose immunosuppressive therapy followed by autologous hematopoietic cell transplant. Along with the loss of capillaries there was a dramatic change in endothelial phenotype in the residual vessels. The molecules defining this phenotype are: vascular endothelial cadherin, a supposedly universal endothelial marker required for tube formation (lost in the scleroderma tissue), antiangiogenic interferon α (overexpressed in the scleroderma dermis) and RGS5, a signaling molecule whose expression coincides with the end of branching morphogenesis during development and tumor angiogenesis (also overexpressed in scleroderma skin. Following high dose immunosuppressive therapy, patients experienced clinical improvement and 5 of the 7 patients with scleroderma had increased capillary counts. It was also observed in the same 5 patients, that the interferon α and vascular endothelial cadherin had returned to normal as other clinical signs in the skin regressed, and in all 7 patients, RGS5 had returned to normal.Conclusion/SignificanceThese data provide the first objective evidence for loss of vessels in scleroderma and show that this phenomenon is reversible. Coordinate changes in expression of three molecules already implicated in angiogenesis or anti-angiogenesis suggest that control of expression of these three molecules may be the underlying mechanism for at least the vascular component of this disease. Since rarefaction has been little studied, these data may have implications for other diseases characterized by loss of capillaries including hypertension, congestive heart failure and scar formation.

Expression of platelet-derived growth factor B-chain and platelet-derived growth factor β-receptor in fibroblasts of scleroderma

Scleroderma is a fibrotic disease occurring in a localized or systemic form. The pathogenesis of scleroderma remains poorly understood. Recent studies revealed that various cytokines and growth factors were involved in the development of scleroderma fibrosis. Platelet-derived growth factor (PDGF) is a potent growth factor for mesenchymal cells, especially fibroblasts. It can promote fibroblasts proliferation, enhance extracellular matrix synthesis. It is also a chemoattractant to fibroblasts. To better understand the role of PDGF in pathogenesis of scleroderma, we performed both in vivo studies on the expression of PDGF β-receptor protein in scleroderma tissue and in vitro studies on the expression of PDGF B-chain and PDGF β-receptor mRNA in cultured fibroblasts derived from both lesions of scleroderma and normal skin. Immunohistochemistry staining showed that PDGF β-receptor expression was greatly elevated in the dermis of scleroderma lesion whereas PDGF β-receptor were expressed at low levels in normal skin. Northern blot analysis showed that cultured fibroblasts from scleroderma had higher expression of PDGF B-chain and PDGF β-receptor mRNA than those from normal control. Two PDGF B-chain mRNA transcripts, 2.8 and 4.0 kb, were expressed. The 2.8 kb transcripts which had more efficient translation ability was the more predominantly expressed one. These results indicate that PDGF B-chain/PDGF β-receptor signal pathway might be involved in the development of fibrosis in scleroderma, and that the 2.8 kb PDGF B-chain mRNA transcript may be the main modulation gene.

Myofibroblasts from Scleroderma Skin Synthesize Elevated Levels of Collagen and Tissue Inhibitor of Metalloproteinase (TIMP-1) with Two Forms of TIMP-1

Cultured fibroblasts derived from skin biopsies from scleroderma patients and normal individuals were examined for the presence of smooth muscle alpha-actin, a marker for myofibroblasts. Six of eight scleroderma cell lines were found to be 50% or more positive for alpha-actin while three of four normal lines and one cell line derived from unaffected skin of a scleroderma patient were less than 10% positive. The cultured fibroblasts from affected scleroderma skin were largely myofibroblasts, a phenotype found in biopsies of scleroderma tissue, as well as other fibrotic lesions, wound healing, and tumor desmoplasia. The data support the hypothesis that a certain activated fibroblast phenotype predominates in scleroderma. The activated fibroblast is the myofibroblast. Both collagen and TIMP (tissue inhibitor of metalloproteinases) were elevated in the alpha-actin positive (myofibroblast enriched) cultures. In addition, the myofibroblast-enriched cultures displayed a more prominent TIMP doublet band pattern on SDS-polyacrylamide gel electrophoresis.

Activation of Dermal Connective Tissue in Scleroderma

Systemic scleroderma is an acquired disorder which typically results in fibrosis of the skin and internal organs. The pathogenesis of systemic scleroderma is characterized by three distinct processes: microvascular alterations including capillary endothelial cell injury, perivascular inflammatory reaction in dermis, and excessive accumulation of collagen in the dermal layer of lesional skin. In this review, molecular mechanisms resulting in activation of collagen synthesis by dermal fibroblasts in scleroderma are discussed. Specifically, the role of inflammatory cells and the cytokines/growth factors produced by these cells in the pathogenesis of scleroderma is emphasized. The possibilities for prevention and resolution of tissue fibrosis on the basis of these observations are also discussed. Understanding the pathogenetic mechanisms of scleroderma at a molecular level is likely to provide possibilities for development of more specific therapeutic modalities for this and other fibrotic disorders.

Control of fibrosis in systemic scleroderma.

Scleroderma is characterized by an excessive deposition of collagen in all involved organs. This is due to an overproduction of extracellular matrix (ECM) molecules following induction of gene expression, whereas there is no evidence that the composition of the connective tissue matrix is altered. Several in vivo studies and in vitro experiments suggest that a close interaction between inflammatory cells and fibroblasts is required for the initial activation of fibroblasts. TGF-beta presumably plays an important role, but other cytokines, e.g., PDGF or FGF, may also be involved. Many of the ECM molecules have been shown to interact closely with fibroblasts and provide signals that regulate fibroblast metabolism. The cellular response towards those signals is a further aspect of fibrosis that has attracted attention during recent years. The altered expression of receptor proteins on the cell surface of scleroderma fibroblasts for example might explain in part the lack of down-regulation of collagen synthesis in late phases of the disease. This review summarizes the alterations of connective tissue in scleroderma, and discusses the role of cytokines as well as the ECM for the regulation of fibroblast function and their implication for the development of fibrosis.

The Connective Tissue in Scleroderma

The Connective Tissue in Scleroderma

Connective tissue in scleroderma. A biochemical study on the correlation of fractionated glycosaminoglycans and collagen in human skin

No abstract available