Bone Marrow-Derived Progenitor Cells in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy

Abstract

Background and Purpose— Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited disease due to cerebral microangiopathy presenting with variable pictures, including stroke, progressive cognitive impairment, and disability. Mechanisms leading from vessel structural changes to parenchymal damage and eventually to clinical expression are not fully understood. Among pathogenic processes, endothelial dysfunction has been hypothesized. Endothelial progenitor cells and circulating progenitor cells (CPCs) derived from bone marrow participate in endothelium structure and function maintenance and contribute to ischemic area revascularization. No data are available about these cells in CADASIL. Our objective in this study was to evaluate endothelial progenitor cells and CPCs role in CADASIL. Methods— Twenty-nine patients with CADASIL and 29 sex- and age-matched control subjects were enrolled. Cells were measured in peripheral blood using flow cytometry. Endothelial progenitor cells were defined as positive for CD34/KDR, CD133/KDR, and CD34/CD133/KDR; and CPCs as positive for CD34, CD133, and CD34/CD133. Results— Endothelial progenitor cells were significantly lower in patients with CADASIL than in control subjects (CD34/KDR: 0.05 versus 0.1 cells/μL, P =0.005; CD133/KDR: 0.07 versus 0.1 cells/μL, P =0.006; CD34/CD133/KDR: 0.05 versus 0.1 cells/μL, P =0.001). The difference remained significant after adjusting for age, sex, and statin use. CPCs were not significantly lower in CADASIL, but patients with stroke or dementia had significantly reduced CPC levels than patients without (CD34: 1.68 versus 2.95 cells/μL, P =0.007; CD133: 1.40 versus 2.82 cells/μL, P =0.004; CD34/CD133: 1.44 versus 2.75 cells/μL, P =0.004). CPC levels significantly correlated with cognitive and motor performance measures. Conclusions— We have documented an association between endothelial progenitor cells and CPCs and CADASIL, extending previous data about the presence of endothelial dysfunction in this disease and its potential role in modulating phenotype.

Circulating biologic markers of endothelial dysfunction in cerebral small vessel disease: A review

“…Moreover, in CADASIL, CPC levels were associated with clinical/functional indicators of disease severity, suggesting that these cells might have a role in the determination of the final phenotypic expression of the disease. 90 Data heterogeneity may be explained by a number of differences in studies design. A first major concern relates to the different cohorts under investigation: some studies were conducted in the framework of population-based surveys of elderly individuals, while others investigated hospital cohorts without age limits.…”

Stem cell factor and granulocyte colony-stimulating factor exhibit therapeutic effects in a mouse model of CADASIL

“…In other words, the "yellow capillaries" may be the results of endothelial damage by CADASIL-associated cerebral capillary degeneration, and the damaged endothelium is replaced by the bone marrow-derived endothelial cells. In support of this notion, a clinical study showed that the levels of endothelial progenitor cells (EPCs) in the blood of CADASIL patients were significantly lower than in control subjects, and that CADASIL patients with infarcts and dementia displayed a reduction in circulating progenitor cells (Pescini et al, 2010). The reduction of circulating EPCs in CADASIL may be due to the persistent consumption of EPCs to replace the damaged endothelium during the progressive degeneration of cerebral vessels.…”

New Vessels after Stroke: Postischemic Neovascularization and Regeneration

“…In cerebrovascular medicine, other recent studies demonstrated low levels of circulating EPCs in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [30], a correlation between low EPC levels and severe age-related white matter changes [31] and higher levels in patients with moyamoya disease [32]. …”