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

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.

Disulfiram Suppressed Peritendinous Fibrosis Through Inhibiting Macrophage Accumulation and Its Pro-inflammatory Properties in Tendon Bone Healing

“…However, the role of DSF on macrophage is unknown. In TI, the functional phenotype change of M1 and M2 exhibits a phagocytic and pro-inflammatory function, which plays an important role in the healing process ( Chamberlain et al, 2021 ; Yu et al, 2021 ). Furthermore, the reduced macrophage-mediated inflammation in the injured tendon through M1-to-M2 transmission significantly inhibits adhesion formation during tendon healing ( Dong et al, 2021 ).…”

Noncoding RNAs: Master Regulator of Fibroblast to Myofibroblast Transition in Fibrosis

“…and ultimately promote the expression of fibrosis-related genes. ncRNA in the MAPK Pathway miR-21 [87], miR-127-3p [88], miR-43 [23], miR-32-5p [89], miR-338-3p [90], miR-155 [91], miR-22 [92], miR-503 [78], lncRNA FENDRR [93], and circEP400 [94] can affect the activation of the MAPK signaling pathway and regulate the differentiation of fibroblasts into myofibroblasts. We found that most of these ncRNAs did not directly target molecules in the MAPK pathway but targeted some proteins regulating the MAPK signaling pathway, such as PDCD4, DUSP1, SPRY1, etc.…”

A “cell-free treatment” for tendon injuries: adipose stem cell-derived exosomes

“…In turn, macrophage-derived exosomes promote fibrosis after tendon injury mainly through the MIR-15b-5p/FGF-1/7/9 pathway in the context of mediating circRNA-Ep400, which not only reveals the mechanism of association between macrophages and stromal cells, but also explores the role of exosomes in the process of tendon adhesion. However, further experiments are still required to verify their effectiveness on scar adhesion [ 38 , 39 ].…”