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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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Capillary Counts Increase After HDIT and HCT Compared to Baseline and to Scleroderma of Long Duration.Data are average “profiles”/hpf counted in scleroderma patients before (Baseline) and after (After HDIT/HCT) treatment with HDIT and HCT. “Late disease” are average “profiles”/hpf in a separate group of patients with disease duration similar to patients after HDIT/HCT, included to provide an additional disease control. Baseline (biopsies for patients who grew back capillaries) had an average capillary number of 4.1/hpf. After HDIT/HCT, average capillary number (for patients who increased capillary number) rose to 5.8/hpf (p = 0.015). Patients with a disease duration of 5 or more years averaged 3.8 profiles/hpf and when compared with the patients who grew back capillaries(After HDIT/HCT) yielded a p value of 0.025.
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pone-0001452-g005: Capillary Counts Increase After HDIT and HCT Compared to Baseline and to Scleroderma of Long Duration.Data are average “profiles”/hpf counted in scleroderma patients before (Baseline) and after (After HDIT/HCT) treatment with HDIT and HCT. “Late disease” are average “profiles”/hpf in a separate group of patients with disease duration similar to patients after HDIT/HCT, included to provide an additional disease control. Baseline (biopsies for patients who grew back capillaries) had an average capillary number of 4.1/hpf. After HDIT/HCT, average capillary number (for patients who increased capillary number) rose to 5.8/hpf (p = 0.015). Patients with a disease duration of 5 or more years averaged 3.8 profiles/hpf and when compared with the patients who grew back capillaries(After HDIT/HCT) yielded a p value of 0.025.

Mentions: To demonstrate whether capillary counts increase after treatment, we quantified biopsies from the scleroderma patients who grew back capillaries at baseline and after HDIT/HCT. Patients after HDIT/HCT show significantly increasing capillary numbers (p = 0.015, Figure 5). Most interesting, because of the mechanistic implications, is the correlation of the capillary numbers with VE cadherin and interferon α expression. All 7 patients showed changes in interferon α and VE cadherin in baseline biopsies. In the 5 patients where capillary counts increased, IHC for VE cadherin was positive in all vessels (Table 4). In the same patients where VE cadherin expression returned to normal, IFNA1 and IFNA2 in situ hybridization (interferon α) was undetectable (Table 4, see Figure 4 C for photomicrographs).


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)

Capillary Counts Increase After HDIT and HCT Compared to Baseline and to Scleroderma of Long Duration.Data are average “profiles”/hpf counted in scleroderma patients before (Baseline) and after (After HDIT/HCT) treatment with HDIT and HCT. “Late disease” are average “profiles”/hpf in a separate group of patients with disease duration similar to patients after HDIT/HCT, included to provide an additional disease control. Baseline (biopsies for patients who grew back capillaries) had an average capillary number of 4.1/hpf. After HDIT/HCT, average capillary number (for patients who increased capillary number) rose to 5.8/hpf (p = 0.015). Patients with a disease duration of 5 or more years averaged 3.8 profiles/hpf and when compared with the patients who grew back capillaries(After HDIT/HCT) yielded a p value of 0.025.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0001452-g005: Capillary Counts Increase After HDIT and HCT Compared to Baseline and to Scleroderma of Long Duration.Data are average “profiles”/hpf counted in scleroderma patients before (Baseline) and after (After HDIT/HCT) treatment with HDIT and HCT. “Late disease” are average “profiles”/hpf in a separate group of patients with disease duration similar to patients after HDIT/HCT, included to provide an additional disease control. Baseline (biopsies for patients who grew back capillaries) had an average capillary number of 4.1/hpf. After HDIT/HCT, average capillary number (for patients who increased capillary number) rose to 5.8/hpf (p = 0.015). Patients with a disease duration of 5 or more years averaged 3.8 profiles/hpf and when compared with the patients who grew back capillaries(After HDIT/HCT) yielded a p value of 0.025.
Mentions: To demonstrate whether capillary counts increase after treatment, we quantified biopsies from the scleroderma patients who grew back capillaries at baseline and after HDIT/HCT. Patients after HDIT/HCT show significantly increasing capillary numbers (p = 0.015, Figure 5). Most interesting, because of the mechanistic implications, is the correlation of the capillary numbers with VE cadherin and interferon α expression. All 7 patients showed changes in interferon α and VE cadherin in baseline biopsies. In the 5 patients where capillary counts increased, IHC for VE cadherin was positive in all vessels (Table 4). In the same patients where VE cadherin expression returned to normal, IFNA1 and IFNA2 in situ hybridization (interferon α) was undetectable (Table 4, see Figure 4 C for photomicrographs).

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