Abstract
Arsenite (As), a notorious toxic metal, is ubiquitously distributed in the earth and poses a serious threat to human health. Histopathological lesions of As intoxication are known as thromboangiitis obliterans, which are resistant to current treatment and often lead to lower limb amputation. In this study, we attempt to find that treatment with mesenchymal stem cells (MSCs) may be effective for As-induced vasculopathy. We first conducted an in vitro study with a co-culture system containing human MSCs and human umbilical vein endothelial cells (HUVECs) and treated individual and co-cultured cells with various concentrations of arsenite. We also designed an in vivo study in which Sprague Dawley (SD) rats received periodic intraperitoneal (IP) injections of 16 ppm arsenite for 12 weeks. MSCs were harvested from BALB/c mice that were transplanted via tail vein injection. We found that there was significantly higher cellular viability in human mesenchymal stem cells (hMSCs) than in HUVECs under concentrations of arsenite between 15 and 25 μM. The Annexin V apoptosis assay further confirmed this finding. Cytokine array assay for As-conditioned media revealed an elevated vascular endothelial growth factor (VEGF) level secreted by MSCs, which is crucial for HUVEC survival and was evaluated by an siRNA VEGF knockdown test. In the in vivo study, we demonstrated early apoptotic changes in the anterior tibial vessels of As-injected SD rats with a Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, but these apoptotic changes were less frequently observed upon MSCs transplantation, indicating that the cytoprotective effect of MSCs successfully protected against As-induced peripheral vasculopathy. The feasibility of MSCs to treat and /or prevent the progression of As-induced vasculopathy is justified. Further clinical studies are required to demonstrate the therapeutic efficacy of MSCs in patients suffering from As intoxication with vasculopathy.
Highlights
Toxic metals pose serious adverse effects to the environment and human health
The results showed that there were distinct viability differences between human MSCs (hMSCs) and human umbilical vein endothelial cells (HUVECs) when treated with arsenite for 48 h
By stepping up the dosage of arsenite, we found that there were significantly higher survival rates in hMSCs than in HUVECs at a high concentration of arsenite between 15 to 25 μm
Summary
Toxic metals pose serious adverse effects to the environment and human health Among these metals, arsenite (As) is most commonly found due to its ubiquitous distribution in the earth’s crust [1]. Chronic exposure to arsenite leads to skin lesions, neurological dysfunction, atherosclerosis and cancer [3]. A majority of lesions are located on lower extremities and the condition is called black foot disease, a prevalent endemic disease in Taiwan [8] Treatment for such troublesome complications has been researched for decades and toxic metal-induced vascular diseases are still difficult to treat, often eventually leading to amputation
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