BMSC-derived exosomes promote tendon-bone healing after anterior cruciate ligament reconstruction by regulating M1/M2 macrophage polarization in rats

• Published in: Stem cell research & therapy Vol. 13; no. 1; pp. 1 - 295
• Main Authors: Li, Zhenyu, Li, Qingxian, Tong, Kai, Zhu, Jiayong, Wang, Hui, Chen, Biao, Chen, Liaobin
• Format: Journal Article
• Language: English
• Published: London BioMed Central Ltd 15.07.2022; BioMed Central; BMC
• Subjects: Anterior cruciate ligament; Arthritis; Bioinformatics; Biological response modifiers; Bone healing; Bone marrow; Bone marrow stromal cell; Cartilage; Collagen; Collagen (type II); Computed tomography; Exosome; Exosomes; Experiments; Femur; Inflammation; Interferon; Interferon regulatory factor; Interferon regulatory factor 1; Joint and ligament injuries; Knee; Laboratory animals; Macrophage polarization; Macrophages; Mechanical properties; Medical research; MicroRNA; miRNA; Orthopedic surgery; Osteoarthritis; Polarization; Rotator cuff; Stem cells; Tendon-bone healing; Tibia; Tunnels; China; United States > US
• DOI: 10.1186/s13287-022-02975-0
• ISSN: 1757-6512

Background Recent studies have shown that bone marrow stromal cell-derived exosomes (BMSC-Exos) can be used for tissue repair. However, whether the BMSC-Exos can promote tendon-bone healing after anterior cruciate ligament reconstruction (ACLR) is still unclear. In this study, we observed in vivo and in vitro the effect of rat BMSC-Exos on tendon-bone healing after ACLR and its possible mechanism. Methods Highly expressed miRNAs in rat BMSC-Exos were selected by bioinformatics and verified in vitro. The effect of overexpressed miRNA in BMSC-Exos on M2 macrophage polarization was observed. A rat model of ACLR was established. The experimental components were divided into three groups: the control group, the BMSC-Exos group, and the BMSC-Exos with miR-23a-3p overexpression (BMSC-Exos mimic) group. Biomechanical tests, micro-CT, and histological staining were performed for analysis. Results Bioinformatics analysis showed that miR-23a-3p was highly expressed in rat BMSC-Exos and could target interferon regulatory factor 1 (IRF1, a crucial regulator in M1 macrophage polarization). In vitro, compared with the control group or the BMSC-Exos group, the BMSC-Exos mimic more significantly promoted the polarization of macrophages from M1 to M2. In vivo, at 2 weeks, the number of M2 macrophages in the early local stage of ACLR was significantly increased in the BMSC-Exos mimic group; at 4 and 8 weeks, compared with the control group or the BMSC-Exos group, the bone tunnels of the tibia and femur sides of the rats in the BMSC-Exos mimic group were significantly smaller, the interface between the graft and the bone was narrowed, the bone volume/total volume ratio (BV/TV) increased, the collagen type II alpha 1 level increased, and the mechanical strength increased. Conclusions BMSC-Exos promoted M1 macrophage to M2 macrophage polarization via miR-23a-3p, reduced the early inflammatory reaction at the tendon-bone interface, and promoted early healing after ACLR. Keywords: Bone marrow stromal cell, Exosome, Macrophage polarization, Tendon-bone healing, miRNA