The Effect And Safety Of Placenta-derived Mesenchymal Stem Cells In The Treatment Of Ischemic Peripheral Vascular Disease In Diabetic Patients

Objective:We sought to examine the efficacy and safety of intramuscular injection of placenta-derived mesenchymal stem cells(P-MSCs)in diabetic patients with critical limb ischemia in this pilot study.Methods:Four type 2 diabetic patients with ischemic peripheral vascular disease were recruited in this study.A dosage of P-MSCs(1×10~6/kg)was divided into around 50 portions that were administered by multiple deep intramuscular injection into the bilateral gastrocnemius,soleus,and plantar muscles of the four patients.All patients accepted successive three times of P-MSCs transplantation treatment with an interval of 4 weeks for each time.In addition to P-MSCs treatment,all patients received standard?of?care treatment during the 24-weeks follow-up period.Results:At the end of 24-week follow-up,subjective indicators(main ischemic symptoms,including pain,cool feeling,intermittent claudication)were improved significantly after implantation.The ulcer healing rate was 67.7%(2 of 3).The mean of resting ankle-brachial index(ABI)significantly was increased from(0.86±0.20)to(0.95±0.09).Magnetic resonance angiography(MRA)or computed tomography angiography(CTA)demonstrated that there was one patient whose score of new vessels exceeded or equaled to 3 after P-MSCs treatment.Lower limb amputation rate was 25%(1/4).The placenta-derived mesenchymal stem cells can secrete significantly higher angiogenesis-related cytokines under hypoxic conditions,such as vascular endothelial growth factor(VEGF),hepatocyte growth factor(HGF),basic fibroblast growth factor(bFGF),The ELASE analysis showed that placenta-derived mesenchymal stem cells can promote the angiogenesis in the ischemic area,thereby improving the function.The placental-derived mesenchymal stem cells can reduce apoptosis,infiltration of inflammatory cytokines in the ischemic area.Only one patient experienced a mild chill and a fever(temperature 38.3?)two hours after injection at her first time of transplantation.No subjects had a serious adverse event such as infection of the injection site,allergic reactions,liver and renal damage,and abnormal findings of tumor markers during the 24-weeks follow-up period.Conclusion:The data in this pilot study indicate that multiple intramuscular P-MSCs can alleviate critical limb ischemia in diabetic patients,and might be a safe and effective alternative therapy for diabetic ischemia peripheral artery disease,and its mechanism may be related to vascular endothelial cell differentiation and autocrine/paracrine angiogenic cytokines,and also can reduce infiltration of inflammatory cytokines..Placental-derived mesenchymal stem cells can paracrine significantly higher activity of angiogenesis–related cytokines in hypoxic environment:vascular endothelial growth factor(VEGF),hepatocyte growth factor(HGF),basic fibroblast growth factor(bFGF).Although there are some limitations such as a small sample size,lack of control group,etc.,these observations in the present study prompted the need for a larger,placebo?controlled,perspective study to evaluate the efficacy and safety of P-MSCs treatment in diabetic patients with ischemia peripheral artery disease.