Abstract
Critical limb ischemia (CLI), an end-stage manifestation of peripheral artery disease (PAD), still lacks effective therapeutic strategies. Recently, dental pulp-derived mesenchymal stem cells (DP-MSCs) have been attracting more and more attentions in therapeutic applications due to their high proliferation ability, powerful osteogenic differentiation potential, and effective anti-inflammatory effects. In this study, we compared the therapeutic effects of MSCs derived from different sources in a femoral artery-ligated preclinical ischemic model. We found that treatments with MSCs, including bone marrow- (BM-), adipose- (AD-), dental pulp- (DP-), and umbilical cord- (UC-) derived MSCs, improved limb functions, reduced inflammatory responses, increased angiogenesis, and promoted regeneration of muscle fiber. Among them, DP-MSCs and BM-MSCs produced much more impressive effects in restoring limb functions and promoting angiogenesis. The flow velocity restored to nearly 20% of the normal level at 3 weeks after treatments with DP-MSCs and BM-MSCs, and obvious capillary proliferation and collateral development could be observed. Although neovascularization was induced in the ischemic limb after ligation, MSCs, especially DP-MSCs, significantly enhanced the angiogenesis. In vitro experiments showed that serum deprivation improved the expression of angiogenic factors, growth factors, and chemokines in DP-MSCs and UC-MSCs, but not in BM-MSCs and AD-MSCs. However, DP-MSCs produced stronger therapeutic responses than UC-MSCs, which might be due to the higher expression of hepatocyte growth factor (HGF) and hypoxia-inducible factor-1 α (HIF-1α). We speculated that DP-MSCs might stimulate angiogenesis and promote tissue repair via expressing and secreting angiogenic factors, growth factors, and chemokines, especially HGF and HIF-1α. In conclusion, DP-MSCs might be a promising approach for treating CLI.
Highlights
Peripheral artery disease (PAD), an atherosclerotic arterial occlusive disease, is characterized by ischemia in the lower extremities [1]
We found that Mesenchymal stem cell (MSC) transplantations promoted tissue repair and angiogenesis effectively in a rat ischemic model
Studies demonstrated that adiposederived MSCs (AD-MSCs) promoted angiogenesis in ischemic heart and cerebral diseases and peripheral vascular disease, via secreting angiogenic factors including Vascular Endothelial Cell Growth Factor (VEGF), basic fibroblast growth factor (bFGF), IL-6, and transforming growth factor α (TGF-α) [32, 33]
Summary
Peripheral artery disease (PAD), an atherosclerotic arterial occlusive disease, is characterized by ischemia in the lower extremities [1]. 1% to 2% of patients with PAD will develop to critical limb ischemia (CLI), an end-stage manifestation of PAD always accompanied by chronic ischemic rest pain, impaired wound healing, and ulceration of the foot [4, 5]. The therapy of limb ischemia mainly relies on surgical revascularization. 50% of the CLI patients are not suitable for surgical revascularization due to the intricate vascular occlusions, severe comorbidity, sepsis, limb gangrene, and so on [6]. It is estimated that only about 25% of CLI patients can benefit from surgical treatments. It is urgent to develop effective strategies to prevent amputation and to reduce death in patients with no treatment options
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