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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.

SUBMITTER: Li L

PROVIDER: S-EPMC7656701 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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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.

Li Lu L Wang Yikai Y Yu Xiaobing X Bao Yongming Y An Lijia L Wei Xiaowei X Yu Weiting W Liu Baoyi B Li Junlei J Yang Jiahui J Xia Yan Y Liu Ge G Cao Fang F Zhang Xiuzhi X Zhao Dewei D

Stem cell research & therapy 20201111 1

<h4>Background</h4>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.<h4>Methods</h4>To verify the hypothesis that BMMSCs could promote thrombus formation in a paracrine manner, we colle ...[more]

PMID: 33176873

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Project description:ObjectivesBone microvascular endothelial cells (BMECs) played an important role in the pathogenesis of glucocorticoid-induced osteonecrosis of femoral head (GCS-ONFH), and exosomes derived from bone marrow mesenchymal stem cells (BMSC-Exos) may provide an effective treatment. This study aimed to evaluate the effects of BMSC-Exos and internal microRNA-210-3p (miRNA-210) on GCS-ONFH in an in vitro hydrocortisone-induced BMECs injury model and an in vivo rat GCS-ONFH model.MethodsBMECs, BMSCs and BMSC-Exos were isolated and validated. BMECs after the treatment of hydrocortisone were cocultured with different concentrations of BMSC-Exos, then proliferation, migration, apoptosis and angiogenesis of BMECs were evaluated by CCK-8, Annexin V-FITC/PI, cell scratch and tube formation assays. BMSCs were transfected with miRNA-210 mimics and miRNA-210 inhibitors, then BMSC-ExosmiRNA-210 mimic and BMSC-ExosmiRNA-210 inhibitor secreted from such cells were collected. The differences between BMSC-Exos, BMSC-ExosmiRNA-210 mimic and BMSC-ExosmiRNA-210 inhibitor in protecting BMECs against GCS treatment were analyzed by methods mentioned above. Intramuscular injections of methylprednisolone were performed on Sprague-Dawley rats to establish an animal model of GCS-ONFH, then tail intravenous injections of BMSC-Exos, BMSC-ExosmiRNA-210 mimic or BMSC-ExosmiRNA-210 inhibitor were conducted after methylprednisolone injection. Histological and immunofluorescence staining and micro-CT were performed to evaluate the effects of BMSC-Exos and internal miRNA-210 on the in vivo GCS-ONFH model.ResultsDifferent concentrations of BMSC-Exos, especially high concentration of BMSC-Exos, could enhance the proliferation, migration and angiogenesis ability and reduce the apoptosis rates of BMECs treated with GCS. Compared with BMSC-Exos, BMSC-ExosmiRNA-210 mimic could further enhance the proliferation, migration and angiogenesis ability and reduce the apoptosis rates of BMECs, while BMECs in the GCS + BMSC-ExosmiRNA-210 inhibitor group showed reduced proliferation, migration and angiogenesis ability and higher apoptosis rates. In the rat GCS-ONFH model, BMSC-Exos, especially BMSC-ExosmiRNA-210 mimic, could increase microvascular density and enhance bone remodeling of femoral heads.ConclusionsBMSC-Exos containing miRNA-210 could serve as potential therapeutics for protecting BMECs and ameliorating the progression of GCS-ONFH.

Project description:ObjectiveTo investigate the efficacy and safety of core decompression (CD) with local administration of zoledronate and enriched bone marrow mononuclear cells (BMMCS) for the treatment of non-traumatic osteonecrosis of femoral head (ONFH).MethodsA total of 17 patients (30 hips) diagnosed with stage II and III ONFH according to the 2019 revised Association for Research on Osseous Circulation (ARCO) staging criteria from 2012 to 2014 were retrospectively reviewed. The patients received the following therapy: the BMMCs and zoledronate were injected into the necrotic zone, respectively, along with CD. The mean age of the patients was 36.8 years; 14 were men and three were women. All patients included had non-traumatic ONFH and a minimum follow-up of 5 years, which ended when total hip arthroplasty (THA) was performed. Imaging modalities, including plain radiography, computed tomography (CT), and magnetic resonance imaging (MRI) were taken pre- and postoperatively. Harris hip score (HHS) was used to evaluate the functional outcomes of femoral head necrosis. Kaplan-Meier analysis was adopted to determine the probability of survivorship with THA as the end point in this series of patients. The correlation between radiological progression or THA and related risk factors were further analyzed. All complications were recorded.ResultsWith THA as the follow-up endpoint, All patients were followed up for an average of 69.1 ± 20.5 months (range, 18-95 months). Preoperative imaging found six hips (20%) at ARCO stage II, 14 hips (46.7%) at stage IIIA, 10 hips (33.3%) at stage IIIB. Fourteen hips (46.7%) shown progression radiologically, while six hips (20%) underwent TKA among these patients with hip preservation. The cumulative survival was 80% (95% CI, 0.608-905) at 5 years with THA as the end point. HHS improved from 63.3 ± 8.7 preoperatively to 74.6 ± 20.6 postoperatively (P = 0.000). Radiological progression was found to be associated with ARCO stage, Japanese Investigation Committee (JIC) type, and corticosteroid exposure (P = 0.047; P = 0.012; P = 0.031). However, no correlation was found between conversion to THA and the known risk factors. No major complication was reported, with only four patients complaining about general weakness and muscle soreness, and all disappeared within 2-3 days.ConclusionsThe novel treatment modality could relieve pain, delay the progression of collapse, which might be an effective and safe method for hip preservation of early and mid-term ONFH. However, the effect of this method may be related to ARCO stage, JIC type, and corticosteroid exposure.

Dataset Information

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.

Publications

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.

Similar Datasets

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