Increased BMSC exosomal miR-140-3p alleviates bone degradation and promotes bone restoration by targeting Plxnb1 in diabetic rats

Abstract

Background Diabetes mellitus (DM) is considered to be an important factor for bone degeneration disorders such as bone defect nonunion, which is characterized by physical disability and tremendous economy cost to families and society. Exosomal miRNAs of BMSCs have been reported to participate in osteoblastogenesis and modulating bone formation. However, their impacts on the development of bone degeneration in DM are not yet known. The role of miRNAs in BMSCs exosomes on regulating hyperglycemia bone degeneration was investigated in the present study. Results The osteogenic potential in bone defect repair of exosomes derived from diabetes mellitus BMSCs derived exosomes (DM-Exos) were revealed to be lower than that in normal BMSCs derived exosomes (N-Exos) in vitro and in vivo. Here, we demonstrate that miR-140-3p level was significantly altered in exosomes derived from BMSCs, ADSCs and serum from DM rats. In in vitro experiments, upregulated miR-140-3p exosomes promoted DM BMSCs differentiation into osteoblasts. The effects were exerted by miR-140-3p targeting plxnb1, plexin B1 is the receptor of semaphoring 4D(Sema4D) that inhibited osteocytes differentiation, thereby promoting bone formation. In DM rats with bone defect, miR-140-3p upregulated exosomes were transplanted into injured bone and accelerated bone regeneration. Besides, miR-140-3p in the exosomes was transferred into BMSCs and osteoblasts and promoted bone regeneration by targeting the plexin B1/RohA/ROCK signaling pathway. Conclusions Normal-Exos and miR-140-3p overexpressed-Exos accelerated diabetic wound healing by promoting the osteoblastogenesis function of BMSCs through inhibition plexin B1 expression which is the receptor of Sema4D and the plexin B1/RhoA/ROCK pathway compared with diabetes mellitus-Exos. This offers a new insight and a new therapy for treating diabetic bone unhealing. Graphical Abstract

MiR-21 regulating PVT1/PTEN/IL-17 axis towards the treatment of infectious diabetic wound healing by modified GO-derived biomaterial in mouse models

“…Adipose-derived mesenchymal stem cells (AD-MSCs) are a more effective source of stem cells with a higher capacity for migration, proliferation, and differentiation, compared with bone marrow-derived MSCs (BM-MSCs) [ 10 – 12 ]. Benefiting from their paracrine secretion, AD-MSCs are enabled to initiate a repairing process of progenitor-cell populations, such as upregulating immune response and proangiogenic factors [ 13 , 14 ].…”

Pathogenesis and treatment of wound healing in patients with diabetes after tooth extraction

“…For pigs and mice, anti-angiogenic MiR-92a, its inhibitor, possesses the ability to accelerate wound healing (97). In in vitro experiments, upregulated MiR-140-3p exosomes promoted the differentiation of MSCs into osteoblasts (98).…”

Mesenchymal Stem Cell-Derived Extracellular Vesicles for Bone Defect Repair

“…Previous studies have revealed that miRNAs contained in Exos are the main regulators that promote osteogenic differentiation [ 129 ]. Wang et al [ 130 ] showed that the ability of T 2 DM rat-derived BMSC-Exos to promote osteogenic differentiation was significantly impaired, while up-regulating the level of miR-140-3p in Exos could restore its normal osteogenic ability. Further studies revealed that plxnb1 is a direct downstream mRNA target of miR-140-3p, which is closely related to bone formation.…”