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Capillary regeneration in scleroderma: stem cell therapy reverses phenotype?

Fleming JN, Nash RA, McLeod DO, Fiorentino DF, Shulman HM, Connolly MK, Molitor JA, Henstorf G, Lafyatis R, Pritchard DK, Adams LD, Furst DE, Schwartz SM - PLoS ONE (2008)

Bottom Line: Along with the loss of capillaries there was a dramatic change in endothelial phenotype in the residual vessels.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Washington, Seattle, Washington, United States of America. flemij@u.washington.edu

ABSTRACT

Background: Scleroderma 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 findings: We 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 alpha (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 alpha 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/significance: These 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.

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Endothelial Phenotype of Capillaries in Scleroderma Compared to Normal Controls.Markers of normal endothelium: A.) CD31 staining highlights capillaries in both scleroderma and normal controls. B.) Black arrows show Ulex europaeus lectin (Ulex) is lost from some vessels in scleroderma (compare with CD31 above). C.) VE Cadherin stain is lost from some vessels in scleroderma (arrows) whereas all vessels in normal skin are positive for VE cadherin. Both von Willebrand factor and alkaline phosphatase were similarly lost from scleroderma were similarly lost from scleroderma (data not shown) Markers of inflamed endothelium: D.) CD123, a marker for high endothelial venules, is increased in scleroderma as is E.) smooth muscle actin (SMA). In the capillaries (arrows) smooth muscle actin stain extends to the very top of the dermal papilla, unlike normal skin where smooth muscle actin stain ends at the superficial horizontal plexus (doubleheaded arrow). SMA staining is also increased in the media of vessels in the reticular dermis, (data not shown)
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pone-0001452-g001: Endothelial Phenotype of Capillaries in Scleroderma Compared to Normal Controls.Markers of normal endothelium: A.) CD31 staining highlights capillaries in both scleroderma and normal controls. B.) Black arrows show Ulex europaeus lectin (Ulex) is lost from some vessels in scleroderma (compare with CD31 above). C.) VE Cadherin stain is lost from some vessels in scleroderma (arrows) whereas all vessels in normal skin are positive for VE cadherin. Both von Willebrand factor and alkaline phosphatase were similarly lost from scleroderma were similarly lost from scleroderma (data not shown) Markers of inflamed endothelium: D.) CD123, a marker for high endothelial venules, is increased in scleroderma as is E.) smooth muscle actin (SMA). In the capillaries (arrows) smooth muscle actin stain extends to the very top of the dermal papilla, unlike normal skin where smooth muscle actin stain ends at the superficial horizontal plexus (doubleheaded arrow). SMA staining is also increased in the media of vessels in the reticular dermis, (data not shown)

Mentions: Figure 1 (A and B) depicts normal and scleroderma biopsies where serial sections have been stained with CD31 and Ulex europaeus lectin. In scleroderma skin a population of vessels have no luminal staining for Ulex europaeus lectin whereas normal skin has robust staining in all vessels. Von Willebrand factor, VE cadherin (Figure 1 C), and alkaline phosphatase all showed similar marked loss of luminal stain.


Capillary regeneration in scleroderma: stem cell therapy reverses phenotype?

Fleming JN, Nash RA, McLeod DO, Fiorentino DF, Shulman HM, Connolly MK, Molitor JA, Henstorf G, Lafyatis R, Pritchard DK, Adams LD, Furst DE, Schwartz SM - PLoS ONE (2008)

Endothelial Phenotype of Capillaries in Scleroderma Compared to Normal Controls.Markers of normal endothelium: A.) CD31 staining highlights capillaries in both scleroderma and normal controls. B.) Black arrows show Ulex europaeus lectin (Ulex) is lost from some vessels in scleroderma (compare with CD31 above). C.) VE Cadherin stain is lost from some vessels in scleroderma (arrows) whereas all vessels in normal skin are positive for VE cadherin. Both von Willebrand factor and alkaline phosphatase were similarly lost from scleroderma were similarly lost from scleroderma (data not shown) Markers of inflamed endothelium: D.) CD123, a marker for high endothelial venules, is increased in scleroderma as is E.) smooth muscle actin (SMA). In the capillaries (arrows) smooth muscle actin stain extends to the very top of the dermal papilla, unlike normal skin where smooth muscle actin stain ends at the superficial horizontal plexus (doubleheaded arrow). SMA staining is also increased in the media of vessels in the reticular dermis, (data not shown)
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2175530&req=5

pone-0001452-g001: Endothelial Phenotype of Capillaries in Scleroderma Compared to Normal Controls.Markers of normal endothelium: A.) CD31 staining highlights capillaries in both scleroderma and normal controls. B.) Black arrows show Ulex europaeus lectin (Ulex) is lost from some vessels in scleroderma (compare with CD31 above). C.) VE Cadherin stain is lost from some vessels in scleroderma (arrows) whereas all vessels in normal skin are positive for VE cadherin. Both von Willebrand factor and alkaline phosphatase were similarly lost from scleroderma were similarly lost from scleroderma (data not shown) Markers of inflamed endothelium: D.) CD123, a marker for high endothelial venules, is increased in scleroderma as is E.) smooth muscle actin (SMA). In the capillaries (arrows) smooth muscle actin stain extends to the very top of the dermal papilla, unlike normal skin where smooth muscle actin stain ends at the superficial horizontal plexus (doubleheaded arrow). SMA staining is also increased in the media of vessels in the reticular dermis, (data not shown)
Mentions: Figure 1 (A and B) depicts normal and scleroderma biopsies where serial sections have been stained with CD31 and Ulex europaeus lectin. In scleroderma skin a population of vessels have no luminal staining for Ulex europaeus lectin whereas normal skin has robust staining in all vessels. Von Willebrand factor, VE cadherin (Figure 1 C), and alkaline phosphatase all showed similar marked loss of luminal stain.

Bottom Line: Along with the loss of capillaries there was a dramatic change in endothelial phenotype in the residual vessels.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Washington, Seattle, Washington, United States of America. flemij@u.washington.edu

ABSTRACT

Background: Scleroderma 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 findings: We 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 alpha (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 alpha 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/significance: These 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.

Show MeSH
Related in: MedlinePlus