M2 Macrophagy-derived Exosomal MiRNA-5106 Induces Bone Mesenchymal Stem Cells towards Osteoblastic Fate by Targeting Salt-inducible Kinase 2 and 3

Abstract

Background Osteoblast differentiation is a vital process for fracture healing, and exosomes are nanosized membrane vesicles that can deliver therapeutic drugs easily and safely. Macrophages participate in the regulation of various biological processes in vivo , and macrophage-derived exosomes (MD-Exos) have recently been a topic of increasing research interest. However, few study has explored the link between MD-Exos and osteoblast differentiation. Herein, we sought to identify miRNAs differentially expressed between M1 and M2 macrophage-derived exosomes, and to evaluate their roles in the context of osteoblast differentiation. Results We found that microRNA-5106 (miR-5106) was significantly overexpressed in M2 macrophage-derived exosomes (M2D-Exos), while its expression was decreased in M1 macrophage-derived exosomes (M1D-Exos), and we found that this exosomal miRNA can induce bone mesenchymal stem cell (BMSC) osteogenic differentiation via directly targeting the Salt-inducible kinase 2 and 3 ( SIK2 and SIK3 ) genes. In addition, the local injection of both a miR-5106 agonist or M2D-Exos to fracture sites was sufficient to accelerate healing in vivo . Conclusions Our study demonstrates that miR-5106 is highly enriched in M2D-Exos, and that it can be transferred to BMSCs wherein it targets SIK2 and SIK3 genes to promote osteoblast differentiation.

M2 macrophage‐derived exosomal miR‐25‐3p improves high glucose‐induced podocytes injury through activation autophagy via inhibiting DUSP1 expression

“…11,12 Several lines of evidence implicated that macrophage participates in the progression of various diseases through secreting exosomes. 13 In earlier study, Tesch et al pointed out the number of macrophage in kidney is related to the serious of DN, damage of renal function and DN prognosis. They further revealed that the macrophage activation facilitates the degradation of the kidney function.…”

“…M1 macrophage promotes the development of DN through secreting pro‐inflammatory cytokines like IL‐1, IL‐6, and TNF‐α, while M2 macrophage inhibits the development of DN through secreting anti‐inflammatory cytokines as IL‐10 and Arg‐1 11,12 . Several lines of evidence implicated that macrophage participates in the progression of various diseases through secreting exosomes 13 . In earlier study, Tesch et al pointed out the number of macrophage in kidney is related to the serious of DN, damage of renal function and DN prognosis.…”

M1 macrophage‐derived exosomes aggravate bone loss in postmenopausal osteoporosis via a microRNA‐98/DUSP1/JNK axis

“…Mφ‐derived exosomes account for a large portion of circulating microvesicles in the blood (McDonald et al, 2014). M2Mφ‐derived exosomes have been reported to induce osteoblastic fate in bone mesenchymal stem cells (Xiong et al, 2020). However, in a recent study by Jiang et al (2018), bone marrow stem cell‐derived exosomes from OP patients inhibited osteogenesis by transporting miR‐21 into cells.…”

Magnetically-Targeted Nanoparticle-Guided M2 Macrophage Polarization For Fracture Healing Promotion

“…Research has highlighted the promising use of nanomedicine in osteogenic differentiation, with recent years seeing a surge in the development of nanomedicines for bone repair, in an effort to overcome the weaknesses of currently available strategies [13][14][15]. A number of nano-drug delivery systems have been designed to effectively locally deliver various drugs into fracture sites, with improved drug concentration and decreased side-effects [16][17][18].…”