Exosomes derived from human CD34+ stem cells transfected with miR-26a prevent glucocorticoid-induced osteonecrosis of the femoral head by promoting angiogenesis and osteogenesis

Abstract

Background: Damaged endothelial cells and downregulated osteogenic ability are two key pathogenic mechanisms of glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH). Recent studies suggested that transplantation of CD34 + stem cell-derived exosomes (CD34 +-Exos) can treat ischemic diseases by promoting neovascularization and that miR-26a is an important positive regulator of osteogenesis. Moreover, the biological effect of exosomes is closely related to their cargo miRNAs. However, it is not clear whether increasing the abundance of miR-26a in CD34 +-Exos will inhibit the progress of GC-induced ONFH. Methods: MiR-26a was overexpressed in CD34 +-Exos (miR-26a-CD34 +-Exos) to increase their osteogenic potential. The angiogenic potential of miR-26a-CD34 +-Exos was then examined through evaluations of migration and tubeforming capacities in vitro. In addition, in order to observe the osteogenic effect of miR-26a-CD34 +-Exos on bone marrow stromal cells (BMSCs), Alizarin red staining, alkaline phosphatase (ALP) activity assays, and qPCR were carried out. Finally, miR-26a-CD34 +-Exos were injected into a GC-induced ONFH rat model to prevent the progress of GCinduced ONFH. The biological effects of miR-26a-CD34 +-Exos on the ONFH model were evaluated by micro-CT, angiography, and histological staining. Results: Our data showed that miR-26a-CD34 +-Exos enhanced human umbilical vein endothelial cell migration and tube-forming capacities. Furthermore, miR-26a-CD34 +-Exos strengthened the osteogenic differentiation of BMSCs under the influence of GCs in vitro. Finally, the miR-26a-CD34 +-Exos increased the vessel density and trabecular bone integrity of the femoral head in the GC-induced ONFH rat model, which inhibited the progress of ONFH. Conclusions: MiR-26a-CD34 +-Exos protect the femoral head from damage caused by GCs by strengthening angiogenesis and osteogenesis. The biological effect of miR-26a-CD34 +-Exos make them suitable for application in the prevention of GC-induced ONFH.

microRNA‐148a‐3p in extracellular vesicles derived from bone marrow mesenchymal stem cells suppresses SMURF1 to prevent osteonecrosis of femoral head

“…30 Moreover, miR-26a-CD34-EVs strengthened the osteogenic differentiation of BMSCs and the integrity of trabecular bone in glucocorticoids-induced ONFH. 31 miR-148a was found to differentially expressed in BMSC-EVs. 9 Notably, miR-148-3p is down-regulated in BMSCs of ONFH mice.…”

“…For instance, miR‐122‐5p overexpressed in BMSC‐derived EVs suppresses the expression of RTK signalling antagonist 2 to inhibit the occurrence of ONFH through RTK/Ras/mitogen‐activated protein kinase axis 30 . Moreover, miR‐26a‐CD34‐EVs strengthened the osteogenic differentiation of BMSCs and the integrity of trabecular bone in glucocorticoids‐induced ONFH 31 . miR‐148a was found to differentially expressed in BMSC‐EVs 9 .…”

Exosomal miR-100-5p Inhibits Osteogenesis of BMSCs and Angiogenesis of VECs By Suppressing BMPR2/Smad1/5/9 Signaling Pathway

“…Exosomes derived from different mesenchymal stem cells has been reported to be a popular area of research for the treatment of NONFH 9,25,27 . The most popular therapeutic mechanisms of multiple MSC-derived exosomes were promoting osteogenic differentiation BMSCs and angiogenic differentiation of VECs.…”

“…The impaired osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and angiogenesis of vascular endothelial cells (VECs) are considered as the main factors leading to the initiation and progression of NONFH 8,9 . BMSCs, with high proliferative potential and the ability to differentiate into osteoblasts, chondrocytes and adipocytes, are considered as the precursor cells of osteoblasts and play an important role in bone growth, regeneration and reconstruction 10 .…”

MicroRNA-205 mediates endothelial progenitor functions in distraction osteogenesis by targeting the transcription regulator NOTCH2

“…Specific miRNAs have been shown to control the balance been pro-and antiangiogenic activity in a range of contexts [14], and there is also experimental evidence suggesting the importance of miRNAs as regulators of angiogenic-osteogenic coupling [15]. For example, miR-9 [16], miR-26a [17], and miR-210 [18] have all been shown to be drivers of angiogenesis and osteogenesis, while miR-10a [19,20], miR-200b [21], and miR-497-195 cluster members [22] can suppress these same processes. As such, specific miRNAs likely control angiogenesis in the context of DO and may represent potent therapeutic targets that can be leveraged to promote bone development.…”