Extracellular vesicles derived from CD73 modified human umbilical cord mesenchymal stem cells ameliorate inflammation after spinal cord injury.

BACKGROUND: Spinal cord injury (SCI) is an inflammatory condition, and excessive adenosine triphosphate (ATP) is released into the extracellular space, which can be catabolized into adenosine by CD73. Extracellular vesicles have been designed as nano drug carriers in many diseases. However, their impacts on delivery of CD73 after SCI are not yet known. We aimed to construct CD73 modified extracellular vesicles and explore the anti-inflammatory effects after SCI. METHODS: CD73 engineered extracellular vesicles (CD73+ hucMSC-EVs) were firstly established, which were derived from human umbilical cord mesenchymal stem cells (hucMSCs) transduced by lentiviral vectors to upregulate the expression of CD73. Effects of CD73+ hucMSC-EVs on hydrolyzing ATP into adenosine were detected. The polarization of M2/M1 was verified by immunofluorescence. Furthermore, A2aR and A2bR inhibitors and A2bR knockdown cells were used to investigate the activated adenosine receptor. Biomarkers of microglia and levels of cAMP/PKA were also detected. Repetitively in vivo study, morphology staining, flow cytometry, cytokine analysis, and ELISA assay, were also applied for verifications. RESULTS: CD73+ hucMSC-EVs reduced concentration of ATP and promoted the level of adenosine. In vitro experiments, CD73+ hucMSC-EVs increased macrophages/microglia M2:M1 polarization, activated adenosine 2b receptor (A2bR), and then promoted cAMP/PKA signaling pathway. In mice using model of thoracic spinal cord contusion injury, CD73+ hucMSC-EVs improved the functional recovery after SCI through decreasing the content of ATP in cerebrospinal fluid and improving the polarization from M1 to M2 phenotype. Thus, the cascaded pro-inflammatory cytokines were downregulated, such as TNF-α, IL-1ß, and IL-6, while the anti-inflammatory cytokines were upregulated, such as IL-10 and IL-4. CONCLUSIONS: CD73+ hucMSC-EVs ameliorated inflammation after spinal cord injury by reducing extracellular ATP, promoting A2bR/cAMP/PKA pathway and M2/M1 polarization. CD73+ hucMSC-EVs might be promising nano drugs for clinical application in SCI therapy.

Characteristics analysis of segmental and regional lumbar spontaneous compensation post thoracic fusion in Lenke 1 and 2 adolescent idiopathic scoliosis.

OBJECTIVE: To explore the characteristics of compensation of unfused lumbar region post thoracic fusion in Lenke 1 and 2 adolescent idiopathic scoliosis. BACKGROUND: Preserving lumbar mobility in the compensation is significant in controlling pain and maintaining its functions. The spontaneous correction of the distal unfused lumbar curve after STF has been widely reported, but previous study has not concentrated on the characteristics of compensation of unfused lumbar region post thoracic fusion. METHOD: A total of 51 Lenke 1 and2 AIS patients were included, whose lowest instrumented vertebrae was L1 from January 2013 to December 2019. For further analysis, demographic data and coronal radiographic films were collected before surgery, at immediate erect postoperatively and final follow-up. The wedge angles of each unfused distal lumbar segments were measured, and the variations in each disc segment were calculated at the immediate postoperative review and final follow-up. Meanwhile, the unfused lumbar curve was divided into upper and lower parts, and we calculated their curve angles and compensations. RESULTS: The current study enrolled 41 females (80.4%) and 10 males (19.6%). Thirty-six patients were Lenke type 1, while 15 patients were Lenke type 2. The average main thoracic Cobb angle and thoracolumbar/lumbar Cobb angle were 44.1 ± 7.7°and 24.1 ± 9.3°, preoperatively. At the final follow-up, the disc wedge angle variation of L1/2, L2/3, L3/4, L4/5 and L5/S1 was 3.84 ± 5.96°, 3.09 ± 4.54°, 2.30 ± 4.53°, - 0.12 ± 3.89° and - 1.36 ± 2.80°, respectively. The compensation of upper and lower coronal lumbar curves at final follow-up were 9.22 ± 10.39° and - 1.49 ± 5.14°, respectively. CONCLUSION: When choosing L1 as the lowest instrumented vertebrae, the distal unfused lumbar segments' compensation showed a decreasing trend from the proximal end to the distal end. The adjacent L1/2 and L2/3 discs significantly contributed to this compensation.

Cholestyramine alleviates bone and muscle loss in irritable bowel syndrome via regulating bile acid metabolism.

Irritable bowel syndrome (IBS) is a widespread gastrointestinal disorder known for its multifaceted pathogenesis and varied extraintestinal manifestations, yet its implications for bone and muscle health are underexplored. Recent studies suggest a link between IBS and musculoskeletal disorders, but a comprehensive understanding remains elusive, especially concerning the role of bile acids (BAs) in this context. This study aimed to elucidate the potential contribution of IBS to bone and muscle deterioration via alterations in gut microbiota and BA profiles, hypothesizing that cholestyramine could counteract these adverse effects. We employed a mouse model to characterize IBS and analysed its impact on bone and muscle health. Our results revealed that IBS promotes bone and muscle loss, accompanied by microbial dysbiosis and elevated BAs. Administering cholestyramine significantly mitigated these effects, highlighting its therapeutic potential. This research not only confirms the critical role of BAs and gut microbiota in IBS-associated bone and muscle loss but also demonstrates the efficacy of cholestyramine in ameliorating these conditions, thereby contributing significantly to the field's understanding and offering a promising avenue for treatment.

Microneedle/CD-MOF-mediated transdural controlled release of methylprednisolone sodium succinate after spinal cord injury.

A new method of transdural delivering drugs to the spinal cord has been developed, involving the use of microneedles (MNs) and a ß-cyclodextrin metal-organic framework (CD-MOF). This epidural microneedle array, dubbed MNs@CD-MOF@MPSS, can be utilized to deliver methylprednisolone sodium succinate (MPSS) to the site of spinal cord injury (SCI) in a controlled manner. MNs allows to generate micropores in the dura for direct drug delivery to the spinal cord, overcoming tissue barriers and targeting damaged regions. Additionally, the CD-MOF provides a secondary extended release after separating from the MNs. In in vitro study, inward MNs increased cellular absorption of MPSS and then reduced LPS-induced M1 polarization of microglia. And animal studies have shown that this method of drug delivery results in improved BMS scores and a reduction in M1 phenotype microphage and glial scar formation. Furthermore, the downregulation of the NLRP3-positive inflammasome and related pro-inflammatory cytokines was observed. In conclusion, this new drug platform has potential for clinical application in spinal cord diseases and is a valuable composite for minimally transdural controlled drug delivery. STATEMENT OF SIGNIFICANCE: This research presents a new epidural microneedle patch made up of microneedles (MNs) and a ß-cyclodextrin metal-organic framework (CD-MOF). The epidural microneedle patch boasts high drug loading capacity, the ability to penetrate the dura, and controlled release. When loaded with methylprednisolone sodium succinate (MPSS), it effectively reduces inflammation and improves neurological function after spinal cord injury. Therefore, it is a novel and promising drug platform for the treatment of spinal cord diseases in a clinical setting.

Assessment of sagittal spinopelvic alignment in asymptomatic Chinese juveniles and adolescents: a large cohort study and comparative meta-analysis.

STUDY DESIGN: Retrospective study and comparative meta-analysis. OBJECTIVE: To document the sagittal spinopelvic alignment in a large cohort study in asymptomatic Chinese juveniles and adolescents, and to explore whether these parameters were different from various regions using meta-analysis. METHODS: Medical records of 656 asymptomatic Chinese juveniles and adolescents were reviewed, whose mean age was 13.14 ± 3.41 years old, including 254 male and 402 female volunteers. Demographic and lateral radiological parameters were evaluated. Furthermore, a systematic online search was performed to identify eligible studies. Weight mean difference (WMD) with 95% confidence interval (CI) were used to evaluate whether these sagittal parameters were different from various regions. RESULTS: The mean value of sagittal spinopelvic alignment in this study was calculated and analyzed respectively. Significant differences of PI (34.20 ± 4.00 vs. 43.18 ± 7.12, P < 0.001) and PT (3.99 ± 6.04 vs. 8.42 ± 7.08, P < 0.001) were found between juveniles and adolescents. A total of 17 studies were recruited for meta-analysis. For juvenile populations, TK, PI and SS of Caucasians were significantly larger than those of our study (all P < 0.001). As for adolescent populations, PI (P = 0.017), TK (P = 0.017) and SS (P < 0.001) of Caucasians was found to be greater when compared with that of our study. All in all, TK, PI and SS in Chinese pre-adult populations were significantly smaller than those populations in Caucasian regions (all P < 0.001). CONCLUSION: Our study was the first large-scale study that reported the mean values of sagittal parameters in asymptomatic Chinese juveniles and adolescents. There were significant differences in TK, PI and SS between our study and other previous reported populations, which reminded us for using specific mean values in different populations when restoring a relatively normal sagittal spinopelvic balance in spinal deformity.