Down‐regulation of exosomal microRNA‐224‐3p derived from bone marrow–derived mesenchymal stem cells potentiates angiogenesis in traumatic osteonecrosis of the femoral head

Abstract

Traumatic osteonecrosis of the femoral head (ONFH) is a condition leading to the collapse of the femoral head, and the primary treatment is a total hip replacement, which has a poor prognosis. The current study was conducted with the aim of investigating the role of exosomes from bone marrow‐derived mesenchymal stem cells (BM‐MSCs) carrying microRNA‐224‐3p (miR‐224‐3p) in traumatic ONFH. Initially, a microarray analysis was performed to screen the differentially expressed genes and miRs associated with traumatic ONFH. Patients with traumatic and nontraumatic ONFH were enrolled, and HUVECs were obtained. The BM‐MSCs‐derived exosomes were purified and characterized, after which HUVECs were cocultured with exosomes. The functional role of miR‐224‐3p in traumatic ONFH was determined using ectopic expression, depletion, and reporter assay experiments. Endothelial cell proliferation, migration, invasion abilities, and angiogenesis were evaluated. Based on microarray analysis, miR‐224‐3p was found to be down‐regulated, whereas focal adhesion kinase family interacting protein of 200 kDa (FIP200) was up‐regulated in ONFH. Traumatic ONFH exosomes resulted in the up‐regulation of FIP200 and down‐regulation of miR‐224‐3p. FIP200 was confirmed to be a target gene of miR‐224‐3p. Exosomes were internalized by vascular endothelial cells. The down‐regulation of exosomal miR‐224‐3p was observed to promote endothelial cell proliferation, migration, invasion abilities, angiogenesis, and FIP200 expression. In addition, FIP200 overexpression promoted angiogenesis. In summary, the results highly indicated that lower miR‐224‐3p levels in exosomes derived from BM‐MSCs promote angiogenesis of traumatic ONFH by up‐regulating FIP200. The present study provides a potential strategy for the treatment of traumatic ONFH.—Xu, H.‐J., Liao, W., Liu, X.‐Z., Hu, J., Zou, W.‐Z., Ning, Y., Yang, Y., Li, Z.‐H. Down‐regulation of exosomal microRNA‐224‐3p derived from bone marrow‐derived mesenchymal stem cells potentiates angiogenesis in traumatic osteonecrosis of the femoral head. FASEB J. 33, 8055–8068 (2019). http://www.fasebj.org

Mesenchymal stem cell exosomes in bone regenerative strategies—a systematic review of preclinical studies

“…Atelocollagen sponge with PBS NA NR Implantation At day 0 2, 4 weeks 5. No treatment NA NA NA NA 2, 4 weeks Xu [ 56 ] 2019 1. Exosomes from human BM-MSCs NR 400 ​μg Intramuscular injection At day 1 6 weeks 2.…”

“…Increasingly, MSC exosomes have replicated the wide-ranging therapeutic efficacies of MSCs in several injury and disease indications such as myocardial ischemia reperfusion injury [ 29 ], drug-induced liver injury [ 30 ], retinal laser injury [ 31 ], pulmonary hypertension [ 32 ], and graft-versus-host-disease [ 33 , 34 ]. MSC exosomes were also reported to be efficacious in enhancing skeletal muscle regeneration [ 35 , 36 ] ​and more recently cartilage [ 23 , [37] , [38] , [39] , [40] ] and bone regeneration [ [41] , [42] , [43] , [44] , [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] , [54] , [55] , [56] , [57] , [58] , [59] , [60] , [61] , [62] , [63] ].…”

P53 and Parkin co-regulate mitophagy in bone marrow mesenchymal stem cells to promote the repair of early steroid-induced osteonecrosis of the femoral head

“…BMSCs are used to treat early steroid-induced ONFH [43][44][45] ; their survival and stemness in the bone necrotic area are key to the effectiveness of transplantation 46,47 . Studies have revealed an OS microenvironment in the femoral-head necrotic area in which transplanted BMSCs incur a great deal of stress apoptosis and aging, which seriously limits transplantation effectiveness [11][12][13] .…”

Extracellular vesicles derived from different sources of mesenchymal stem cells: therapeutic effects and translational potential

“…At present, many microRNAs contained in exosomes have been revealed to associate with organ repair and other functions. It has been reported that low levels of miR-224-3p in BM-MSCs derived exosomes promote endothelial cell proliferation, migration, invasion, and angiogenesis by targeting focal adhesion kinase family interacting proteins (FIP200) [51]. In a study of renal ischemia/reperfusion injury, researchers found that miR-199a-3p enriched in hBMSC-Exos and down-regulate Sema3A expression, thereby activating the AKT and ERK pathways when delivering to renal cells by exosomes [52].…”