Netrin-1 overexpressing macrophage-derived exosomes promote angiogenesis and nerve repair after peripheral nerve injury in diabetic mice
Wang Qiming
Zhang Xinyi
Huang Qun
Wu Xiaoyu
Liu Junchao
Li Weimin
Lu Xinwu
Qin Jinbao
Abstract：Objective To investigate the effect of Netrin-1 overexpressing macrophage-derived exosomes(N-Exos)on angiogenesis and nerve repair after sciatic nerve injury in type 2 diabetes mellitus(T2DM)mice.Methods Bone marrow-derived macrophages(BMDMs)were isolated from the lower limb bone marrow of mice,and adenovirus transfection was used to induce Netrin-1 overexpression in BMDMs.The phenotype of macrophages after Netrin-1 overexpression was detected,and their exosomes were extracted and identified by transmission electron microscopy,nanoparticle tracking analysis and Western blot.Human umbilical vein endothelial cells(HUVECs)were co-cultured with N-Exos under high-glucose conditions in vitro to detect the effects of N-Exos on the proliferation,apoptosis,migration and tube formation abilities of HUVECs.Eighteen 8-week-old male C57BL/KsJ-db/db mice were randomly divided into three groups:the sciatic nerve injury group(control group),the exosome treatment group(Exos group),and the Netrin-1 overexpressing exosome treatment group(N-Exos group).A sciatic nerve injury model of T2DM mice was established to evaluate the effect of N-Exos on nerve repair after sciatic nerve injury in T2DM mice.Results The cell proliferation rate in the N-Exos group was higher than that in the Exos group and the control group,the 24 h scratch healing rate of HUVECs in the N-Exos group was higher than that in the Exos group and the control group,and the relative cumulative length of tube formation of HUVECs co-cultured with N-Exos was longer than that in the Exos group and the control group(all P＜0.05).TUNEL staining results showed that the number of apoptotic HUVECs was the largest in the control group and the smallest in the N-Exos group.In vivo experiments on T2DM mice confirmed that the relative fluorescence intensity of tumor necrosis factor-α in the injured sciatic nerve in the N-Exos group was lower than that in the control group and the Exos group,the relative fluorescence intensities of myelin basic protein and neurofilament protein were both higher than those in the control group and the Exos group,and the relative fluorescence intensity of CD31 in the injured nerve in the N-Exos group was higher than that in the control group and the Exos group.At 14 d after surgery,the gastrocnemius muscle atrophy index of mice in the N-Exos group was significantly lower than that in the Exos group and the control group[(15.7±1.0)％vs(20.5±0.8)％,(25.7±2.5)％](P=0.001).Conclusion N-Exos can promote angiogenesis and nerve repair after peripheral nerve injury in T2DM mice,which provides new ideas and a theoretical basis for the clinical treatment of peripheral nerve injury in diabetic patients.
Keywords：Peripheral nerve injuryExosomesNetrin-1Angiogenesis
Publication Date：2026-04-18
Online Publishing Date：2026-09-14(First online date of this platform, not the publication date of the document)
Pages：6( 506-511 )