Oxidation Prevents HMGB1 Inhibition on PDGF-Induced Differentiation of Multipotent Vascular Stem Cells to Smooth Muscle Cells: A Possible Mechanism Linking Oxidative Stress to Atherosclerosis

Atherosclerosis is considered as a multifactorial disease in terms of the pathogenic mechanisms. Oxidative stress has been implicated in atherogenesis, and the putative mechanisms of its action include oxidative modification of redox-sensitive signaling factors. High mobility group box 1 (HMGB1) is a key inflammatory mediator in atherosclerosis, but if oxidized it loses its activity. Thus, whether and how it participates in oxidative stress-induced atherosclerosis are not clear. The current study found that exogenous HMGB1 dose-dependently inhibited the proliferation of multipotent vascular stem cells and their differentiation to smooth muscle cells induced by platelet-derived growth factor. But oxidative modification impaired the activity of HMGB1 to produce the effect. The stem cells were regarded as the source of smooth muscle cells in vascular remodeling and neointimal hyperplasia. Therefore, the findings suggested that HMGB1 participated in oxidative stress-induced atherosclerosis presumably by targeting multipotent vascular stem cells.

Abstract 42: Differentiation of Human Multipotent Vascular Stem Cells Contributes to Vascular Diseases

Vascular disease, such as neointimal hyperplasia and atherosclerosis, involves in migration and proliferation of vascular cells in blood vessel wall. It is generally accepted that the de-differentiation of vascular smooth muscle cells (SMCs) contributes to vascular diseases. However, previous studies suggest that resident multipotent vascular stem cells (MVSCs) are also involved in neointima formation. In this study, we isolated MVSCs from the medial layer of human carotid artery and thoracic aorta by explant cultures, characterized these cells, and identified the origin of these vascular cells populated in lesion areas. Human MVSCs could be isolated from healthy and diseased blood vessels, were cloneable, and were positive for stem cell markers SOX10 and SOX17 but not SMC markers α-actin and calponin-1. MVSCs were able to differentiate into neural cells, SMCs and other mesenchymal lineages in vitro. In addition, we examined the location of MVSCs in diseased vascular wall by immunohistochemistry. The majority of cells within tunica media were calponin-positive cells, whereas a small population of cells was proliferative and double positive for SOX10 and Ki67 in the border between tunica intima and media. The number of SOX10+ cells in atherosclerotic lesions was more than that in healthy blood vessels, and some of these cells were double positive for SOX10 and chondrogenic markers. Furthermore, we performed in situ PCR and proximity ligation assays to stain for the epigenetic markers of SMC lineage. The results suggested that SOX10+ cells in cell cultures and tissue sections were not derived from de-differentiated SMCs. In conclusion, these findings support that MVSCs contributes to human vascular diseases.