Augmentation of neovascularization in murine hindlimb ischemia by combined therapy with simvastatin and bone marrow-derived mesenchymal stem cells transplantation

Abstract

ObjectivesWe postulated that combining high-dose simvastatin with bone marrow derived-mesenchymal stem cells (MSCs) delivery may give better prognosis in a mouse hindlimb ischemia model.MethodsMouse hindlimb ischemia model was established by ligating the right femoral artery. Animals were grouped (n = 10) to receive local injection of saline without cells (control and simvastatin groups) or with 5 × 106 MSCs (MSCs group).Animals received either simvastatin (20 mg/kg/d, simvastatin and combination groups) or saline(control and MSCs group) gavages for continual 21 days. The blood flow was assessed by laser Doppler imaging at day 0,10 and 21 after surgery, respectively. Ischemic muscle was harvested for immunohistological assessments and for VEGF protein detection using western blot assay at 21 days post-surgery. In vitro, MSCs viability was measured by MTT and flow cytometry following culture in serum-free medium for 24 h with or without simvastatin. Release of VEGF by MSCs incubated with different doses of simvastatin was assayed using ELISA.ResultsCombined treatment with simvastatin and MSCs induced a significant improvement in blood reperfusion, a notable increase in capillary density, a highest level of VEGF protein and a significant decrease in muscle cell apoptosis compared with other groups. In vitro, simvastatin inhibited MSCs apoptosis and increased VEGF release by MSCs.ConclusionsCombination therapy with high-dose simvastatin and bone marrow-derived MSCs would augment functional neovascularization in a mouse model of hindlimb ischemia.

Induced Pluripotent Stem Cell Transplantation Improves Locomotor Recovery in Rat Models of Spinal Cord Injury: a Systematic Review and Meta-Analysis of Randomized Controlled Trials

“…Second, our subgroup analyses of different cell counts indicated that iPSC at doses of 5×10 5 improve the locomotor recovery of rats with SCI at 1-7 weeks after transplantation. This indicates that the optimal dose for iPSC transplantation is 5×10 5 , which is consistent with the results of earlier studies [33,37], although further relevant studies should be conducted to validate these results. We also found that after transplantation, rats showed better functional recovery in subgroups transplanted with iPSC induced from female (IMR90) human fetal lung fibroblasts, which may survive at the lesion site.…”

A low dose of simvastatin enhanced the therapeutic efficacy of mesenchymal stem cell (MSC) transplantation in skin wound healing in diabetic mice associated with increases in pAkt, SDF-1, and angiogenesis

“…A number of studies have shown that simvastatin could reduce inflammatory infiltration, enhance VEGF production, increase the number of circulating endothelial progenitor cells (EPCs), increase angiogenesis, and improve wound healing in diabetic and nondiabetic models [19–23]. In addition, the immediate effects of simvastatin could improve the efficacy of MSCs, increased VEGF production and increased angiogenesis in hindlimb ischemia, a stroke model and several in vitro models [24–27].…”

Injectable Cell Constructs Fabricated via Culture on a Thermoresponsive Methylcellulose Hydrogel System for the Treatment of Ischemic Diseases

“…Ischemic diseases, including myocardial infarction (MI) and peripheral critical limb ischemia, are common disorders associated with significant morbidity and mortality rates . Clinically, the human myocardium lacks the ability to regenerate following MI, resulting in progressive loss of functional cardiac tissue and successive enlargement of the left ventricular (LV) cavity, thereby impairing heart function .…”

“…Critical limb ischemia, on the other hand, is a peripheral artery disease characterized by insufficient blood flow to the extremities to maintain tissue viability, resulting in significant pain and tissue necrosis . Current treatments include antithrombotic therapy and vascular surgery for limb salvage . However, prognosis for patients with critical limb ischemia remains poor, and the lower extremities often require amputation …”