Bone marrow mesenchymal stem cell-derived exosomes promote plasminogen activator inhibitor 1 expression in vascular cells in the local microenvironment during rabbit osteonecrosis of the femoral head

Abstract

Background Nontraumatic osteonecrosis of the femoral head (NONFH) is a highly disabling orthopedic disease in young individuals. Plasminogen activator inhibitor 1 (PAI-1) has been reported to be positively associated with NONFH. We aimed to investigate the dysregulating PAI-1 in bone marrow mesenchymal stem cells (BMMSCs) and vascular cells in rabbit steroid-induced NONFH. Methods To verify the hypothesis that BMMSCs could promote thrombus formation in a paracrine manner, we collected exosomes from glucocorticoid-treated BMMSCs (GB-Exo) to determine their regulatory effects on vascular cells. microRNA sequencing was conducted to find potential regulators in GB-Exo. Utilizing gain-of-function and knockdown approaches, we testified the regulatory effect of microRNA in exosomes. Results The expression of PAI-1 was significantly increased in the local microenvironment of the femoral head in the ONFH model. GB-Exo promoted PAI-1 expression in vascular smooth muscle cells and vascular endothelial cells. We also revealed that miR-451-5p in GB-Exo plays a crucial role for the elevated PAI-1. Moreover, we identified miR-133b-3p and tested its role as a potential inhibitor of PAI-1. Conclusions This study provided considerable evidence for BMMSC exosomal miR-mediated upregulation of the fibrinolytic regulator PAI-1 in vascular cells. The disruption of coagulation and low fibrinolysis in the femoral head will eventually lead to a disturbance in the microcirculation of NONFH. We believe that our findings could be of great significance for guiding clinical trials in the future.

Review of the Role of Mesenchymal Stem Cells and Exosomes Derived from Mesenchymal Stem Cells in the Treatment of Orthopedic Disease

“…Inhibiting the BMPR2/Smad1/5/9 pathway inhibited osteogenesis of BMSCs, inhibited angiogenesis of HUVECs, and promoted adipogenic differentiation of BMSCs [ 61 ], which identified a new gene target for inhibiting NONFH. CD41-deficient exosomes extracted from necrotic tissue of NONFH can inhibit osteogenic differentiation and migration of MSCs; the target pathway is the ONFH-Exo-CD41-integrin β3-FAK (focal adhesion kinase)-Akt-RUNX2 pathway [ 62 ]. By searching for suppressed miRNA in patients with ONFH, scientists found that miRNA-122-5p targeting SPRY2 (rapid development growth factor homologue 2) through the RTK/Ras/MAPK pathway promoted osteoblast proliferation and differentiation in vitro and inhibited the progression of BMSCs in vivo.…”

Exosomal miR-100-5p inhibits osteogenesis of hBMSCs and angiogenesis of HUVECs by suppressing the BMPR2/Smad1/5/9 signalling pathway

“…To investigate the mechanism of action of NONFH exosomes’ impacts on osteogenesis and angiogenesis, we conducted a miRNA sequence. Many differentially expressed miRNAs were identified in exosomes from multiple MSCs and the broad biological significance importance of exosomal miRNAs on osteogenesis and angiogenesis of NONFH has been investigated, including miR-21, miR-26a, miR-148a-3p, miR-451-5p, and miR-365a-5p [ 18 , 21 , 39 – 41 ]. The downstream target genes of these miRNAs include PTEN, PDCD4 PAI-1, and SAV1.…”

“…Exosomes were reported to influence osteogenic differentiation and angiogenesis to regulate bone reconstruction and homeostasis [ 14 – 17 ]. Recent studies have revealed that exosomes from multiple mesenchymal stem cells (MSCs) could be used for NONFH in rats [ 18 – 21 ]. However, no previous study has reported the effect of exosomes from necrotic bone tissues (NONFH exosomes) on the pathogenesis of NONFH.…”

miR-126-3p-loaded small extracellular vesicles secreted by urine-derived stem cells released from a phototriggered imine crosslink hydrogel could enhance vaginal epithelization after vaginoplasty

“…The Agilent Bioanalyzer 2100 system (Agilent, USA) was used to quantify RNA. The library preparations were analyzed on the illumina Hiseq platform for gene clustering and sequencing as previously described [ 21 ]. The data were obtained from Novogene Bioinformatics Technology (China).…”