Abstract
Moyamoya disease (MMD) is well known to be caused by insufficient cerebral vascular formation. However, the essential pathogenesis has not yet been identified. Using our recently developed technique of generating vasculogenic and anti-inflammatory cultures, we investigated endothelial progenitor cell (EPC) expansion and differentiation under the cytokine milieu generated by the peripheral blood mononuclear cells (PBMNCs) of the operated and non-operated MMD patients. EPC colony forming assay of the cultured PBMNCs disclosed the decline of the definitive EPC colony numbers in the both MMD patients. The level of interleukin-10 (IL-10) was lower in secretory cytokines from the cultured PBMNCs of MMD patients than that in that of controls using a cytometric bead array. The addition of human recombinant IL-10 to PBMNCs cultured from MMD patients restored the EPC colony forming potential of MMD PBMNCs. Following phorbol myristate acetate stimulation of the cultured PBMNCs, flow cytometry revealed a decrease in intracellular IL-10 storage in the main cell populations of the PBMNCs cultured from MMD patients relative to those cultured from controls. The present data provide the expected mechanism of vascular malformation in MMD pathogenesis originated from the insufficient production of IL-10 secreting cells from PBMNCs fostering EPC expansion and differentiation.
Highlights
Moyamoya disease (MMD) is well known to be caused by insufficient cerebral vascular formation
Microscopic results revealed that definitive endothelial progenitor cell (EPC) forming colonies consisted of large spindle-like cells, were more commonly observed in the peripheral blood mononuclear cells (PBMNCs) cultured from controls (8.70/ dish) than in those obtained from healthy controls (0.80/dish) (Fig. 1)
The number of colony-forming definitive cells in the PBMNCs cultured from patients with MMD (2.50/dish) or MMD (1.70/dish) who underwent superficial temporal artery to middle cerebral artery (STA-MCA) operations (MMD-O) was significantly lower than that in the PBMNCs cultured from controls (8.70/dish)(p < 0.01)
Summary
Moyamoya disease (MMD) is well known to be caused by insufficient cerebral vascular formation. Using our recently developed technique of generating vasculogenic and anti-inflammatory cultures, we investigated endothelial progenitor cell (EPC) expansion and differentiation under the cytokine milieu generated by the peripheral blood mononuclear cells (PBMNCs) of the operated and non-operated MMD patients. Elevated plasma levels of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) have been reported, suggesting that the pathology of MMD involves the recruitment of cellular components by humoral and/or paracrine factors and that cytokines are significantly related to the pathophysiology of MMD7,8. Cytokines, such as VEGF and PDGF, do not primarily cause MMD. Circulating EPCs derived from the bone marrow were shown to contribute to postnatal physiological and pathological neovascularisation[10,11]
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