Exosomes derived from M2 macrophages prevent steroid-induced osteonecrosis of the femoral head by modulating inflammation, promoting bone formation and inhibiting bone resorption.

Inflammatory reactions are involved in the development of steroid-induced osteonecrosis of the femoral head(ONFH). Studies have explored the therapeutic efficacy of inhibiting inflammatory reactions in steroid-induced ONFH and revealed that inhibiting inflammation may be a new strategy for preventing the development of steroid-induced ONFH. Exosomes derived from M2 macrophages(M2-Exos) display anti-inflammatory properties. This study aimed to examine the preventive effect of M2-Exos on early-stage steroid-induced ONFH and explore the underlying mechanisms involved. In vitro, we explored the effect of M2-Exos on the proliferation and osteogenic differentiation of bone marrow-derived mesenchymal stem cells(BMMSCs). In vivo, we investigated the role of M2-Exos on inflammation, osteoclastogenesis, osteogenesis and angiogenesis in an early-stage rat model of steroid-induced ONFH. We found that M2-Exos promoted the proliferation and osteogenic differentiation of BMMSCs. Additionally, M2-Exos effectively attenuated the osteonecrotic changes, inhibited the expression of proinflammatory mediators, promoted osteogenesis and angiogenesis, reduced osteoclastogenesis, and regulated the polarization of M1/M2 macrophages in steroid-induced ONFH. Taken together, our data suggest that M2-Exos are effective at preventing steroid-induced ONFH. These findings may be helpful for providing a potential strategy to prevent the development of steroid-induced ONFH.

Decellularized extracellular matrix scaffold seeded with adipose-derived stem cells promotes neurorestoration and functional recovery after spinal cord injury through Wnt/ß-catenin signaling pathway regulation.

Spinal cord injury (SCI) causes tissue destruction and neuronal apoptosis, which impede neural function recovery. Therefore, promoting neuronal regeneration and neural pathway reconstruction is crucial. In this study, a novel and facile decellularized extracellular matrix (dECM) scaffold seeded with adipose-derived stem cells (ADSCs) (dECM scaffolds/ADSCs) was reported. The dECM scaffold maintained the original three-dimensional network structure of spinal cord tissue and contained various small pores.In vitrostudies demonstrated that dECM scaffolds exhibited excellent biocompatibility, facilitated efficient adhesion and proliferation of ADSCs, and promoted the secretion of neurotrophin-3 and neuronal differentiation in the microenvironment after SCI.In vivostudies further showed that dECM scaffolds/ADSCs could alleviate inflammatory and apoptotic reactions, providing a favorable microenvironment for promoting endogenous nerve regeneration rather than glial scars formation, ultimately achieving recovery of hind limb function in rats. Notably, ICG-001 effectively reversed the therapeutic effect of dECM scaffolds/ADSCs, proving that dECM scaffolds/ADSCs promoted functional recovery after SCI by regulating the Wnt/ß-catenin signaling pathway. Overall, dECM scaffolds/ADSCs can simulate the physiological characteristics of the spinal cord and exert neurorestorative potential, providing a new therapeutic strategy for SCI.

Transcriptome-wide association study identifies new susceptibility genes and pathways for spondyloarthritis.

BACKGROUND: Spondyloarthritis (SpA) is a group of multifactorial bone diseases influenced by genetic factors, the environment and lifestyle. However, current studies have found a limited number of SpA-related genes, and the genetic and pathogenic mechanisms of SpA are still unclear. METHODS: A tissue-specific transcriptome-wide association study (TWAS) of SpA was performed using GWAS (including 3966 SpA patients and 448,298 controls) summary data and gene expression weights of whole blood and skeletal muscle. The SpA-associated genes identified by TWAS were further compared with the differentially expressed genes (DEGs) identified in the SpA gene expression profile acquired from the Gene Expression Omnibus database (GEO, GSE58667). Finally, functional enrichment and annotation analyses of the identified genes were performed. RESULTS: The TWAS detected 499 suggestive genes associated with SpA in whole blood and skeletal muscle, such as CTNNAL1 (PSM = 3.04 × 10-2, PWB = 9.58 × 10-3). The gene expression profile of SpA identified 20 candidate genes that overlapped in the TWAS data, such as MCM4 (PTWAS = 1.32 × 10-2, PDEG = 2.75 × 10-2) and KIAA1109 (PTWAS = 3.71 × 10-2, PDEG = 4.67 × 10-2). Enrichment analysis of the genes identified by TWAS identified 93 significant GO terms and 33 KEGG pathways, such as mitochondrion organization (GO: 0007005) and axon guidance (hsa04360). CONCLUSION: We identified multiple candidate genes that were genetically related to SpA. Our study may provide novel clues regarding the genetic mechanism, diagnosis, and treatment of SpA.

Curcumin-Containing polyphosphazene nanodrug for Anti-Inflammation and nerve regeneration to improve functional recovery after spinal cord injury.

The microenvironment of excessive inflammation and the activation of apoptotic signals are primary barriers to neurological recovery following spinal cord injury (SCI). Thus, long-lasting anti-inflammation has become an effective strategy to navigate SCI. Herein, a curcumin (CUR)-containing nanosystem (FCTHPC) with high drug loading efficiency was reported via assembling hydrophobic CUR into cross-linked polyphosphazene (PPZ), and simultaneous loading and coordinating with porous bimetallic polymers for greatly enhanced the water-solubility and biocompatibility of CUR. The nanosystem is noncytotoxic when directing its biological activities. By inhibiting the expression of pro-inflammatory factors (IL-1ß, TNF-α and IL-6) and apoptotic proteins (C-caspase-3 and Bax/Bcl-2), which may be accomplished by activating the Wnt/ß-catenin pathway, the versatile FCTHPC can significantly alleviate the damage to tissues and cells caused by inflammation and apoptosis in the early stage of SCI. In addition, the long-term in vivo studies had demonstrated that FCTHPC could effectively inhibit the formation of glial scars, and simultaneously promote nerve regeneration and myelination, leading to significant recovery of spinal cord function. This study emphasises the promise of the biocompatible CUR-based nanosystem and provides a fresh approach to effectively treat SCI.

A comparison of the biomechanical properties of three different lumbar internal fixation methods in the treatment of lumbosacral spinal tuberculosis: finite element analysis.

There are various internal fixation methods in treating lumbosacral spinal tuberculosis. The study compared the stability and stress distribution in surrounding tissues/implants, such as discs, endplates and screw-rod internal fixation system, etc. when applying three different lumbar internal fixation methods to treat lumbosacral spinal tuberculosis. A finite element model was constructed and validated. The spinal stability was restored using three methods: a titanium cage with lateral double screw-rod fixation (group 1), autologous bone with posterior double screw-rod fixation (group 2), and a titanium cage with posterior double screw-rod fixation (group 3). For comparison, group 4 represented the intact L3-S1 spine. Finally, a load was applied, and the ranges of motion and Von Mises stresses in the cortical endplates, screw-rod internal fixation system and cortical bone around the screws in the different groups were recorded and analyzed. All six ranges of motion (flexion, extension, left/right lateral bending, left/right rotation) of the surgical segment were substantially lower in groups 1 (0.53° ~ 1.41°), 2 (0.68° ~ 1.54°) and 3 (0.55° ~ 0.64°) than in group 4 (4.48° ~ 10.12°). The maximum stress in the screw-rod internal fixation system was clearly higher in group 2 than in groups 1 and 3 under flexion, left/right lateral bending, and left/right rotation. However, in extension, group 1 had the highest maximum stress in the screw-rod internal fixation system. Group 2 had the lowest peak stresses in the cortical endplates in all directions. The peak stresses in the cortical bone around the screws were higher in group 1 and group 2 than in group 3 in all directions. Thus, titanium cage with posterior double screw-rod fixation has more advantages in immediate reconstruction of lumbosacral spinal stability and prevention of screw loosening.

Polyphosphazene nanodrugs for targeting delivery and inflammation responsive release of curcumin to treat acute lung injury by effectively inhibiting cytokine storms.

An excessive inflammatory response induced by cytokine storms is the primary reason for the deterioration of patients with acute lung injury (ALI). Though natural polyphenols such as curcumin (CUR) have anti-inflammation activity for ALI treatment, they often have limited efficacy due to their poor solubility in water and oxidising tendency. This study investigates a highly cross-linked polyphosphazene nano-drug (PHCH) developed by copolymerisation of CUR and acid-sensitive units (4-hydroxy-benzoic acid (4-hydroxy-benzylidene)-hydrazide, D-HBD) with hexachlorotripolyphosphonitrile (HCCP) for improved treatment of ALI. PHCH can prolong the blood circulation time and targeted delivery into lung inflammation sites by enhancing CUR's water dispersion and anti-oxidant properties. PHCH also demonstrates the inflammation-responsive release of CUR in an inflammation environment due to the acid-responsive degradation of hydrazine bonds and triphosphonitrile rings in PHCH. Therefore, PHCH has a substantial anti-inflammation activity for ALI treatment by synergistically improving CUR's water-solubility, bioavailability and biocompatibility. As expected, PHCH attenuates the cytokine storm syndrome and alleviates inflammation in the infected cells and tissues by down-regulating several critical inflammatory cytokines (TNF-α, IL-1ß, and IL-8). PHCH also decreases the expression of p-p65 and C-Caspase-1, inhibiting NLRP3 inflammasomes and suppressing NF-κB signalling pathways. The administrated mice experiments confirmed that PHCH accumulation was enhanced in lung tissue and showed the efficient scavenging ability of reactive oxygen species (ROS), effectively blocking the cytokine storm and alleviating inflammatory damage in ALI. This smart polyphosphazene nano-drug with targeting delivery property and inflammation-responsive release of curcumin has excellent potential for the clinical treatment of various inflammatory diseases, including ALI.

Brachial plexus injury after clavicle fracture operation: a case report and literature review.

BACKGROUND: Open reduction and internal fixation (ORIF) is the preferred choice for treating clavicle fractures. The brachial plexus injury caused by ORIF of a clavicle fracture is very rare. If it is not treated in time, the function of the brachial plexus will be challenging to recover, which will eventually lead to upper limb dysfunction and seriously affect the patient's quality of life. Our team recently used ORIF to treat a patient with a clavicle fracture, who developed brachial plexus injury symptoms after surgery. CASE PRESENTATION: A 34-year-old female patient was admitted to the hospital for 13 h due to the right shoulder movement restriction after a fall. Due to the significant displacement of the fracture, we used ORIF to treat the fracture. The surgery went well. When the anaesthesia effect subsided 12 h after the operation, the patient developed right brachial plexus injury symptoms, decreased right upper limb muscle strength, dysfunction, and hypoesthesia. Symptomatic treatments, such as nourishing nerve and electrical stimulation, were given immediately. Sixty days after the operation, the patient's brachial plexus injury symptoms disappeared, and the function of the right upper limb returned to the preoperative state. CONCLUSIONS: Patients with clavicle fractures usually need to undergo a careful physical examination before surgery to determine whether symptoms of brachial plexus injury have occurred. Anaesthesia puncture requires ultrasound guidance to avoid direct damage to the brachial plexus. When the fracture end is sharp, reset should be careful to prevent nerve stump stabbed. When using an electric drill to drill holes, a depth limiter should be installed in advance to prevent the drill from damaging the subclavian nerve and blood vessels. When measuring the screw depth, the measuring instrument should be close to the bone surface and sink slowly to avoid intense hooks and damage to the brachial plexus. Try to avoid unipolar electrosurgical units to prevent heat conduction from damaging nerves, and bipolar electrocoagulation should be used instead. If symptoms of brachial plexus injury occur after surgery, initial symptomatic treatment is drugs and functional exercise, and if necessary, perform surgical exploration.

Corrigendum to "Injectable muscle-adhesive antioxidant conductive photothermal bioactive nanomatrix for efficiently promoting full-thickness skeletal muscle regeneration" [Bioact Mater, 6(2021)1605-1617].

[This corrects the article DOI: 10.1016/j.bioactmat.2020.11.005.].

Exosomes Secreted from Hypoxia-Preconditioned Mesenchymal Stem Cells Prevent Steroid-Induced Osteonecrosis of the Femoral Head by Promoting Angiogenesis in Rats.

Recent studies have suggested that exosomes exert similar therapeutic effects to those of mesenchymal stem cells (MSCs) in regenerative medicine and MSCs-derived exosomes exhibit therapeutic effects on steroid-induced osteonecrosis of the femoral head (ONFH). Furthermore, reparative functions of exosomes from MSCs are enhanced by hypoxia treatment of the cells. However, there are no related reports about whether exosomes derived from hypoxia-preconditioned MSCs could show better therapeutic effects on steroid-induced ONFH. In vitro, we investigated the effects of hypoxia precondition on exosomes derived from bone marrow mesenchymal stem cells (BMMSCs) from rats and the proangiogenic ability of exosomes derived from hypoxia-preconditioned BMMSCs. In vivo, we investigated the role of exosomes from hypoxia-preconditioned BMMSCs on angiogenesis and protecting osteonecrosis in a rat ONFH model. We found that the potential of the proangiogenic ability of exosomes derived from hypoxia-preconditioned BMMSCs was higher than exosomes derived from BMMSCs cultured under normoxia. Exosomes derived from hypoxia-preconditioned BMMSCs significantly promoted proliferation, migration, vascular endothelial growth factor (VEGF) expression, and tube formation of human umbilical vein endothelial cells (HUVECs) compared with exosomes derived from BMMSCs cultured under normoxia. Administration of exosomes derived from hypoxia-preconditioned BMMSCs significantly prevented bone loss and increased vessel volume in the femoral head compared with exosomes derived from BMMSCs cultured under normoxia. Taken together, our data suggest that exosomes derived from hypoxia-preconditioned BMMSCs exert better therapeutic effects on steroid-induced ONFH by promoting angiogenesis and preventing bone loss.

Recent advances in luminescent materials for super-resolution imaging via stimulated emission depletion nanoscopy.

Stimulated emission depletion (STED) nanoscopy is a promising fluorescence microscopy to detect unresolvable structures at the nanoscale level and then achieve a superior imaging resolution in materials science and biological research. However, in addition to the optimization of the microscope, luminescent materials in STED nanoscopy are also of great significance to obtain imaging, visualization and even long-term tracking at an ultra-high resolution (less than 100 nm), but this is seldom summarized. Based on this consideration, recent progress on STED fluorophores for super-resolution imaging is outlined here, including inorganic fluorophores, fluorescent proteins, organic luminescent materials, aggregation-induced emission (AIE) luminogens, and fluorescent nanoparticles. Characteristics of these aforementioned STED fluorophores are also included and compared to provide a deep understanding of the relationship between the properties in luminescent materials and their performance in STED imaging. According to the results on such luminescent materials, it is anticipated that guidelines to select proper probes and even develop new materials for super-resolution imaging via STED nanoscopy will be provided here, finally promoting the development of super-resolution imaging in both materials science and biological research.

Injectable muscle-adhesive antioxidant conductive photothermal bioactive nanomatrix for efficiently promoting full-thickness skeletal muscle regeneration.

The completed skeletal muscle regeneration resulted from severe injury and muscle-related disease is still a challenge. Here, we developed an injectable muscle-adhesive antioxidant conductive bioactive photothermo-responsive nanomatrix for regulating the myogenic differentiation and promoting the skeletal muscle regeneration in vivo. The multifunctional nanomatrix was composed of polypyrrole@polydopamine (PPy@PDA, 342 ± 5.6 nm) nanoparticles-crosslinked Pluronic F-127 (F127)-polycitrate matrix (FPCP). The FPCP nanomatrix demonstrated inherent multifunctional properties including excellent photothermo-responsive and shear-thinning behavior, muscle-adhesive feature, injectable ability, electronic conductivity (0.48 ± 0.03 S/m) and antioxidant activity and photothermal function. The FPCP nanomatrix displayed better photothermal performance with near-infrared irradiation, which could provide the photo-controlled release of protein (91% ± 2.6% of BSA was released after irradiated 3 times). Additionally, FPCP nanomatrix could significantly enhance the cell proliferation and myogenic differentiation of mouse myoblast cells (C2C12) by promoting the expressions of myogenic genes (MyoD and MyoG) and myosin heavy chain (MHC) protein with negligible cytotoxicity. Based on the multifunctional properties, FPCP nanomatrix efficiently promoted the full-thickness skeletal muscle repair and regeneration in vivo, through stimulating the angiogenesis and myotube formation. This study firstly indicated the vital role of multifunctional PPy@PDA nanoparticles in regulating myogenic differentiation and skeletal muscle regeneration. This work also suggests that rational design of bioactive matrix with multifunctional feature would greatly enhance the development of regenerative medicine.

Methane Saline Ameliorates Traumatic Brain Injury through Anti-Inflammatory, Antiapoptotic, and Antioxidative Effects by Activating the Wnt Signalling Pathway.

OBJECTIVE: Methane saline (MS) can be used to treat many diseases via its anti-inflammatory, antiapoptotic, and antioxidative activities. However, to date, there is no published evidence as to whether MS has any effect on traumatic brain injury (TBI). The Wnt signalling pathway regulates cell proliferation, differentiation, migration, and apoptosis; however, whether the Wnt signalling pathway regulates any effect of MS on TBI is unknown. This study was designed to explore the role of MS in the treatment of TBI and whether the Wnt pathway is involved. METHODS: Sprague-Dawley rats were randomly divided into five groups: sham, TBI, TBI+10 ml/kg MS, TBI+20 ml/kg MS, and TBI+30 ml/kg MS. After induction of TBI, MS was injected intraperitoneally once daily for seven consecutive days. Neurological function was evaluated by the Neurological Severity Score (NSS) at 1, 7, and 14 days after TBI. Haematoxylin-eosin (HE) staining, inflammatory factors, neuron-specific enolase (NSE) staining, oxidative stress, and cell apoptosis were measured and compared 14 d after TBI to identify the optimal dose of MS and to investigate the effect of MS on TBI. In the second experiment, Sprague-Dawley rats were randomly divided into four groups: sham, TBI, TBI+20 ml/kg MS, and TBI+20 ml/kg MS+Dickkopf-1 (DKK-1, a specific inhibitor of the Wnt pathway). NSE, caspase-3, superoxide dismutase (SOD), Wnt3a, and ß-catenin were detected by real-time PCR and Western blotting. The results from each group were compared 14 d after TBI to determine the regulatory role of the Wnt pathway. RESULTS: Methane saline significantly inhibited inflammation, oxidative stress, and cell apoptosis, thus protecting neurons within 14 days of TBI. The best treatment effect against TBI was obtained with 20 ml/kg MS. When the Wnt pathway was inhibited, the treatment effect of MS was impaired. CONCLUSION: Methane saline ameliorates TBI through its anti-inflammatory, antiapoptotic, and antioxidative effects via activation of the Wnt signalling pathway, which plays a part but is not the only mechanism underlying the effects of MS. Thus, MS may be a novel strategy for treating TBI.

Exercise protects against spinal cord injury through miR-21-mediated suppression of PDCD4.

Spinal cord injury (SCI) can lead to different levels of paraplegia. Studies have shown that exercise exerts wide protective effects against various diseases, and microRNAs (miRNAs) are involved in its beneficial effects. However, the specific role of miRNAs in the protective effects of exercise against SCI remains unclear. Here, we showed that exercise exerted protective effects against SCI as evidenced by increased locomotor activity and spinal cord cell survival in rats with SCI. Exercise upregulated circulating miR-21, detected by miRNA microarray, in rats with SCI. Treating SCI rats with agomiR-21 upregulated circulating miR-21 and exerted protective effects against SCI. Additionally, downregulating miR-21 using antagomir-21 abolished the protective effects of exercise on SCI. Programmed cell death protein 4 (PDCD4) was found to be the target of miR-21. These results suggested that exercise protects against SCI, at least partly, through miR-21-mediated suppression of PDCD4.

The Proosteogenic and Proangiogenic Effects of Small Extracellular Vesicles Derived from Bone Marrow Mesenchymal Stem Cells Are Attenuated in Steroid-Induced Osteonecrosis of the Femoral Head.

Small extracellular vesicles (sEVs) derived from bone marrow mesenchymal stem cells (BMMSCs) from individuals with steroid-induced osteonecrosis of the femoral head (ONFH) have not been studied. The objective of the present study was to compare the proosteogenic and proangiogenic effects of sEVs derived from BMMSCs from rats with steroid-induced ONFH (oBMMSCs-sEVs) and sEVs derived from BMMSCs from normal rats (nBMMSCs-sEVs). BMMSCs were isolated from steroid-induced ONFH rats and healthy rats. sEVs were isolated and characterized by Western blotting analysis of exosomal surface biomarkers and by transmission electron microscopy. The impacts of nBMMSCs-sEVs and oBMMSCs-sEVs on the proliferation and osteogenic differentiation of BMMSCs were determined via cell proliferation assay, alizarin red staining, and alkaline phosphatase activity assay. Enzyme-linked immunosorbent assay and tube formation assay were conducted to investigate the effect of nBMMSCs-sEVs and oBMMSCs-sEVs on the angiogenic potential of human umbilical vein endothelial cells (HUVECs). The expression of relevant genes was detected by quantitative real-time polymerase chain reaction analysis, and the expression of ß-catenin was detected by immunofluorescence. Both nBMMSCs-sEVs and oBMMSCs-sEVs promoted proliferation, osteogenic differentiation, and ß-catenin expression of BMMSCs and enhanced angiogenesis of HUVECs. However, compared with nBMMSCs-sEVs, oBMMSCs-sEVs exhibited attenuated effects. Our findings indicated that the proosteogenic and proangiogenic effects of sEVs were partially attenuated in steroid-induced ONFH. Therefore, this study might offer guidance for the selection of source cells for sEV therapy in the future.

"Median paralyzing dose" and "multiple regression analysis", a new viewpoint to the research method of spinal cord injury.

INTRODUCTION: Spinal cord impact is a mature method for building models of spinal cord injury (SCI). However, a common problem is that the degree of elicited paralysis may not be identical even though animals receive the same impact. We hypothesize that this difference may be caused by the difference in the secondary injury mechanism of SCI and there might be an impact dosage named "median paralyzing dose (PD50)", similar as the "median lethal dose (LD50)" in pharmacology. In addition, since SCI is a result of multiple mechanisms, we hypothesize that it is more suitable to employ multiple regression analysis to analyze the related factors for complete paraplegia. So the present study aimed to calculate the existence of PD50 and analyze the related factors of SCI-induced complete paralysis using logistic regression under the PD50 which represents identical primary injury. MATERIAL AND METHODS: Rat models of SCI were built using the weight-drop method under PD50. PD50 was calculated by Karber's method. Rats were allocated into two groups according to whether they developed complete or incomplete paralysis 2 weeks after injury. Cavity and spared tissues in the two groups were compared. Neuronal preservation, microglia/macrophage reaction, T-lymphocyte infiltration, astrocyte activation and neuronal apoptotic were compared by immunohistochemistry. The logistic regression model was constructed and significant related factors of complete paralysis were selected. RESULTS: Of the two groups, the cavity in the injured spinal cord of the complete-paralysis rats was significantly larger and the spared white matter volume (SWMV%) was obviously smaller. Whereas, the spared grey matter volume was not different between groups. Macrophage reaction, T-lymphocyte infiltration and neuronal apoptosis were significantly more severe in the complete-paralysis rats. Astrocyte activation and neuronal preservation showed no difference between groups. Logistic regression analysis showed that cavity volume, SWMV%, microglia/macrophage reaction and neuronal apoptosis were significantly correlated with SCI-induced complete paralysis. CONCLUSION: As a non-mainstream method, it is feasible to analyze the secondary factors of SCI-induced complete paralysis using multiple regression analysis in the condition of identical primary injury (PD50). SWMV% and microglia/macrophage reaction are important factors that contribute to complete paralysis at the early phase of severe SCI.

Protective effect of brain-derived neurotrophic factor and neurotrophin-3 overexpression by adipose-derived stem cells combined with silk fibroin/chitosan scaffold in spinal cord injury.

Objectives: Spinal cord injury (SCI) is a most debilitating traumatic injury, and cytotherapy is a promising alternative treatment strategy. Here we investigated the effect and mechanism of adipose-derived stem/stromal cells (ASCs) with overexpressing brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) (BDNF-NT3) in combination with silk fibroin/chitosan scaffold (SFCS) in SCI.Methods: Female Sprague-Dawley rats were used as an SCI model. SFCS,SFCS and ASCs, or ASCs overexpressing NT3, BDNF, and BDNF-NT3 were implanted into SCI rats. Basso, Beattie, and Bresnahan score, pathological changes, and spinal cord tissue and nerve fiber morphology were observed and assayed. GAP-43, GFAP, and caspase-3 expression was determined using immunohistochemistry and western blotting.Results: Smoother spinal cords, less scar tissue, and lower inflammatory activity were found in the SFCS, SFCS and ASCs, ASCs with NT3, BDNF, and BDNF-NT3 overexpression treatment than in the untreated SCI rat groups. Increasing formation of nerve fibers was observed in the above groups in order. GAP-43 expression significantly increased, while GFAP and caspase-3 expression significantly decreased. These results indicated obvious alleviation in pathological changes and BDNF-NT3 overexpression in ASCs combined with SFCS treatment in SCI rats.Conclusion: Thus, BDNF-NT3 overexpression from ASCs with SFCS had synergistic neuroprotective effects on SCI and may be a treatment option for SCI.

Safe range of shortening the middle thoracic spine, an experimental study in canine.

PURPOSE: To determine the safe range of shortening the spinal column at middle thoracic spine and to observe the changes in blood-spinal cord barrier (BSCB), microglia/macrophage activation and inducible nitric oxide synthase (iNOS) activity after shortening-induced spinal cord injury. METHODS: Dogs were allocated to four groups. Group A (control) underwent laminectomy of T7 without shortening the spinal column. Groups B, C and D had 1/3, 1/2, and 2/3 of T7 resected, respectively, followed by spinal shortening. Somatosensory evoked potential (SSEP) and hind-limb function were recorded periodically for 14 days after operation. Spinal cord blood flow (SCBF) and BSCB were detected at the acute phase of shortening. Microglia/macrophage reactions and iNOS activity were observed by immunohistochemistry. RESULTS: Shortening of 1/3 of a vertebral height caused no significant changes in SSEP and hind-limb function after operation, whereas shortening of 1/2 of the height caused SSEP abnormality and paraparesis, and severe neurologic deficit of hind-limb was observed when the shortening reached 2/3 of the height. SCBF increased temporarily and showed a trend of recovery when the shortening was within 1/2 of a vertebral segment height. When it reached 1/2 or 2/3 of the height, SCBF at 6 h post-operation was 86.33% or 74.95% of the baseline, and an increasing BSCB permeability was observed. In the subsequent 7 days, obvious activation of macrophage and increased number of iNOS-positive cells were observed. CONCLUSION: It is safe to shorten the spinal cord within 1/3 of a vertebral height in middle thoracic spine under two-segment laminectomy in canine. The BSCB disruption, macrophage activation, and increased iNOS activity were observed in the acute phase of the injury. These slides can be retrieved under Electronic Supplementary Material.

miR-21 deficiency contributes to the impaired protective effects of obese rat mesenchymal stem cell-derived exosomes against spinal cord injury.

The therapeutic effect of stem cell transplantation in traumatic spinal cord injury (SCI) has been extensively studied these days, and evidence has shown that stem cell-derived exosomes and exosome-shuttled miRNA (e.g. miR-21) contribute to the protective effects of stem cell transplantation against SCI. It has been reported that obesity, a prevalent metabolic disorder, reshapes stem cells and their extracellular vesicles. However, the effects of exosomes derived from obese rat stem cells on SCI and its underlying mechanism remain unknown. Here, we examined the effects of exosomes derived from obese rat mesenchymal stem cells (MSCs) on SCI, and tested the role of miR-21 in their effects. We found that exosomes derived from obese rat MSCs showed decreased miR-21 levels and did not exert protective effects against SCI. Overexpression of miR-21 in obese rat MSCs restored the protective effects of exosomes purified from obese rat MSCs against SCI. In addition, obese rat MSCs showed insulin resistance, and MSC insulin resistance decreased miR-21 levels in its secreted exosomes. These results suggested that miR-21 deficiency in obese rat MSCs contributes to the impaired protective effects of obese rat MSCs-derived exosomes against SCI, and further reinforced the notion that miR-21 is a potential molecule for treatment of SCI.

BADGE, a synthetic antagonist for PPARγ, prevents steroid-related osteonecrosis in a rabbit model.

BACKGROUND: It was indicated that inhibition of PPARγ probably represents a novel therapy for steroid-related osteonecrosis. In this study, we investigated the preventive effects of PPARγ inhibition on steroid-related osteonecrosis in a rabbit model. METHODS: Rabbits were randomly divided into three groups (normal group, model group and BADGE group). Osteonecrosis was induced in rabbits in the model group and the BADGE group. The BADGE group also received bisphenol a diglycidyl ether(BADGE), a PPARγ antagonist, for 6 weeks. RESULTS: Histopathological results indicated that rabbits treated with BADGE exhibited significantly reduced osteonecrotic changes, incidence of osteonecrosis and bone marrow adiposity. Furthermore, BADGE-treated rabbits exhibited reduced intraosseous pressure and increased femoral blood perfusion. Micro-computed tomography and bone histomorphometry indicated that the BADGE group exhibited significantly improved bone quality and mineral appositional rate compared with the model group. Furthermore, the BADGE group showed a significant increase in circulating levels of the bone formation marker osteocalcin and reduced levels of the bone resorption marker TRACP. Overall, BADGE-treated rabbits exhibited reduced marrow adiposity concomitant with improved bone formation. CONCLUSIONS: In conclusion, these observations demonstrated that pharmacological inhibition of PPARγ might represent an effective therapy for steroid-related osteonecrosis in the near future.

Selected suitable seed cell, scaffold and growth factor could maximize the repair effect using tissue engineering method in spinal cord injury.

Spinal cord injury usually leads to permanent disability, which could cause a huge financial problem to the patient. Up to now there is no effective method to treat this disease. The key of the treatment is to enable the damage zone axonal regeneration and luckily it could go through the damage zone; last a connection can be established with the target neurons. This study attempts to combine stem cell, material science and genetic modification technology together, by preparing two genes modified adipose-derived stem cells and inducing them into neuron direction; then by compositing them on the silk fibroin/chitosan scaffold and implanting them into the spinal cord injury model, seed cells can have features of neuron cells. At the same time, it could stably express the brain-derived neurotrophic factor and neurotrophin-3, both of which could produce synergistic effects, which have a positive effect on the recovery of spinal cord. The spinal cord scaffold bridges the broken end of the spinal cord and isolates with the surrounding environment, which could avoid a scar effect on the nerve regeneration and provide three-dimensional space for the seed cell growth, and at last we hope to provide a new treatment for spinal cord injury with the tissue engineering technique.