Capillary Regeneration in Scleroderma: Stem Cell Therapy Reverses Phenotype?

Abstract

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.

Autologous Fat Grafting in the Treatment of Fibrotic Perioral Changes in Patients with Systemic Sclerosis

“…Besides the action of conditioning immunosuppressive therapy in ablating autoimmune response and strongly reducing fibroblast activation (1), it has been postulated that the ASCT effectiveness can be at least in part ascribed to the capacity of the repopulating stem cells to induce a neoangiogenesis in the sclerotic skin (13,23).…”

Shared Gene Expression Patterns in Mesenchymal Progenitors Derived from Lung and Epidermis in Pulmonary Arterial Hypertension: Identifying Key Pathways in Pulmonary Vascular Disease

“…Microvascular pathology in both lung and skin is also present in systemic sclerosis, which suggests that the skin-derived MCs may share similar gene signatures with lung MPCs and therefore may be exploited to identify changes in the pulmonary vascular bed as well as tissuespecific patterns of protein expression. 4,[33][34][35][36] In order to identify whether the selected gene expression patterns identified were recapitulated in skin MCs, we analyzed gene expression of human skin FBs. Cells were isolated from 5 groups: controls, patients with known BMPR2 mutations but not PAH, patients with known BMPR2 mutations and PAH, patients with IPAH, and patients with CAV1 mutations and PAH.…”

Hematopoietic Cell Transplantation for Autoimmune Diseases: A Review of History, Current State, and Future Issues

“…Therefore, employment of HCT has resulted in rapid and sustained improvement of skin thickening and functional ability, stabilization of major organ function with some improvement of vital capacity in pilot studies, registry analyses, and the phase II-III trials. Some patients have achieved complete remission (CR) including unexpected and dramatic clinical and biopsy regression of dermal fibrosis as well as normalization of the microvasculature [61].…”