Exosomes From M2 Macrophage Promote Peritendinous Fibrosis Posterior Tendon Injury via the MiR-15b-5p/FGF-1/7/9 Pathway by Delivery of circRNA-Ep400.

Yinxian Yu,Zhi Cui,Subin Lin,Chengqing Yi,Mingming Jin,Zhuoying Wang,Mengkai Yang,Binbin Sun

doi:10.3389/fcell.2021.595911

Abstract

Achilles tendon rupture prognosis is usually unsatisfactory. After the tendon is injured, it may not function properly because of the fibrotic healing response, which restrains tendon motion. Inflammatory monocytes and tissue-resident macrophages are indispensable regulators in tissue repair, fibrosis, and regeneration. Exosomes from macrophages are crucial factors in tissue microenvironment regulation following tissue injury. This study therefore aimed to clarify the roles of macrophage exosomes in tendon injury (TI) repair. The results show that macrophages play a role after TI. M1 macrophages were increased relative to peritendinous fibrosis after TI. High-throughput sequencing showed abnormal expression of circular RNAs (circRNAs) between exosomes from M2 and M0 macrophages. Among the abnormal expressions of circRNA, circRNA-Ep400 was significantly increased in M2 macrophage exosomes. The results also show that M2 macrophage-derived circRNA-Ep400-containing exosomes are important for promoting peritendinous fibrosis after TI. Bioinformatics and dual-luciferase reporting experiments confirmed that miR-15b-5p and fibroblast growth factor (FGF)-1/7/9 were downstream targets of circRNA-Ep400. High circRNA-Ep400-containing exosome treatment inhibited miR-15b-5p, but promoted FGF1/7/9 expression in both fibroblasts and tenocytes. Furthermore, high circRNA-Ep400-containing exosome treatment promoted fibrosis, proliferation, and migration in both fibroblasts and tenocytes. Taken together, the results show that M2 macrophage-derived circRNA-Ep400-containing exosomes promote peritendinous fibrosis after TI via the miR-15b-5p/FGF-1/7/9 pathway, which suggests novel therapeutics for tendon injury treatment.

Highlights

Tendon tears and tendinopathies are common musculoskeletal injuries, which contribute to > 30% of musculoskeletal consultations (McCormick et al, 1995)
The results show that M2 macrophage-derived circular RNA (circRNA)-Ep400-containing exosomes are important for promoting peritendinous fibrosis after tendon injury (TI)
The results show that M2 macrophagederived circRNA-Ep400-containing exosomes promote peritendinous fibrosis after TI via the miR-15b-5p/fibroblast growth factor (FGF)-1/7/9 pathway, which suggests novel therapeutics for tendon injury treatment

Summary

Introduction

Tendon tears and tendinopathies are common musculoskeletal injuries, which contribute to > 30% of musculoskeletal consultations (McCormick et al, 1995). Flexor tendon injury (TI) usually occurs during lacerations, and the incidence is highest among patients 20–29 years of age, with a higher incidence in males than in females (de Jong et al, 2014). Of these injuries, tendinopathy has a huge socioeconomic burden, predicted to result in an annual medical cost and indirect lost salary expenditure of approximately $850 billion (Wang et al, 2018). Vascular permeability increases and an influx of inflammatory cells enters the healing site These cells produce a number of cytokines and growth factors that lead to recruitment and proliferation of macrophages and resident tendon fibroblasts. This macrophage to fibroblast-like transition might augment fibrosis by collagen deposition (Haider et al, 2019)

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