Safety and efficacy of injection of exosomes derived from human umbilical cord mesenchymal stem cells in the treatment of limb ischemia: an in-vivo evaluation in mice

BACKGROUND: Exosomes have been recently suggested to promote angiogenesis via some miRNAs and proteins. This study aimed to evalu-ate the safety and efficacy of injection of exosomes derived from human umbilical cord mesenchymal stem cells (hUCMSC-exosomes) in treat-ing limb ischemia in mouse models of acute hindlimb ischemia (HLI).METHODS: Exosomes were isolated from a human umbilical cord mesenchymal stem cell-conditioned medium. BALB/c mice were used to create the HLI models by ligating and excising the femoral artery and vein. The HLI models were randomly grouped into a treatment group (HLI-Exo) and a placebo group (HLI-PBS). In the HLI-Exo group, the mice were injected with 100 mu g of exosomes in 150 mu L of PBS into the ischemic muscle sites, while in the HLI-PBS group, the mice were injected with 150 mu L of PBS. The treatment safety was assessed based on the death rate and body weight changes and the treatment efficacy was based on the footstep count, limb morphology, oxygen saturation (SpO2) level, blood flow, angiogenesis, and muscle tissue structure.RESULTS: The hUCMSC-exosomes yielded positive effects in treating acute HLI. On day 28 after surgery, the proportion of mice with limb injury was significantly reduced in the HLI-Exo group, with 50% of the animals having grade 0 necrosis and 0% having grade IV necrosis. Meanwhile, the proportion of mice with grade 0 and IV necroses was only 22% and 14% in the HLI-PBS group, respectively. The SpO2 level of the HLI-Exo group improved rapidly from day 3 and reached 93.4 +/- 1.9% on day 28, while that in the HLI-PBS group increased slowly and reached 87.6 +/- 4% on day 28. The degree of reperfusion in the HLI-Exo group improved significantly on day 7 compared with that in the HLI-PBS group. In addition, the rate of angiogenesis increase was maintained until day 14 in both groups but increased by nearly threefold in the HLI-Exo group compared with that in the HLI-PBS group. Meanwhile, the muscle tissue structure in the HLI-Exo group recovered more rapidly and returned to normal on day 14 after treatment.CONCLUSIONS: hUCMSC-exosomes are a potential cell-free therapy for HLI, with the ability to repair damage and stimulate angiogenic processes.

Automated summary

This study evaluated the safety and efficacy of exosomes derived from human umbilical cord mesenchymal stem cells (hUCMSC-exosomes) in treating acute hindlimb ischemia (HLI) in mouse models. The results showed that hUCMSC-exosomes had positive effects in treating HLI, including reducing limb injury, improving oxygen saturation level, promoting angiogenesis, and accelerating muscle tissue structure recovery.