Anti-Stress and Anti-ROS Effects of MnOx-Functionalized Thermosensitive Nanohydrogel Protect BMSCs for Intervertebral Disc Degeneration Repair.

Stem cell transplantation has been proven to be a promising strategy for intervertebral disc degeneration (IDD) repair. However, replicative senescence of bone marrow-derived mesenchymal stem cells (BMSCs), shear damage during direct injection, mechanical stress, and the reactive oxygen species (ROS)-rich microenvironment in degenerative intervertebral discs (IVDs) cause significant cellular damage and limit the therapeutic efficacy. Here, an injectable manganese oxide (MnOx)-functionalized thermosensitive nanohydrogel was proposed for BMSC transplantation for IDD therapy. The MnOx-functionalized thermosensitive nanohydrogel not only successfully protected BMSCs from shear force and mechanical stress before and after injection but also repaired the harsh high-ROS environment in degenerative IVDs, thus effectively increasing the viability of BMSCs and resident nucleus pulposus cells (NPCs). The MnOx-functionalized thermosensitive nanohydrogel provides mechanical protection for stem cells and helps to remove endogenous ROS, providing a promising stem cell delivery platform for the treatment of IDD. This article is protected by copyright. All rights reserved.

Piezo1 channel exaggerates ferroptosis of nucleus pulposus cells by mediating mechanical stress-induced iron influx.

To date, several molecules have been found to facilitate iron influx, while the types of iron influx channels remain to be elucidated. Here, Piezo1 channel was identified as a key iron transporter in response to mechanical stress. Piezo1-mediated iron overload disturbed iron metabolism and exaggerated ferroptosis in nucleus pulposus cells (NPCs). Importantly, Piezo1-induced iron influx was independent of the transferrin receptor (TFRC), a well-recognized iron gatekeeper. Furthermore, pharmacological inactivation of Piezo1 profoundly reduced iron accumulation, alleviated mitochondrial ROS, and suppressed ferroptotic alterations in stimulation of mechanical stress. Moreover, conditional knockout of Piezo1 (Col2a1-CreERT Piezo1flox/flox) attenuated the mechanical injury-induced intervertebral disc degeneration (IVDD). Notably, the protective effect of Piezo1 deficiency in IVDD was dampened in Piezo1/Gpx4 conditional double knockout (cDKO) mice (Col2a1-CreERT Piezo1flox/flox/Gpx4flox/flox). These findings suggest that Piezo1 is a potential determinant of iron influx, indicating that the Piezo1-iron-ferroptosis axis might shed light on the treatment of mechanical stress-induced diseases.

Selenium-SelK-GPX4 axis protects nucleus pulposus cells against mechanical overloading-induced ferroptosis and attenuates senescence of intervertebral disc.

Intervertebral disc degeneration (IVDD) is one of the most prevalent spinal degenerative disorders and imposes places heavy medical and economic burdens on individuals and society. Mechanical overloading applied to the intervertebral disc (IVD) has been widely recognized as an important cause of IVDD. Mechanical overloading-induced chondrocyte ferroptosis was reported, but the potential association between ferroptosis and mechanical overloading remains to be illustrated in nucleus pulposus (NP) cells. In this study, we discovered that excessive mechanical loading induced ferroptosis and endoplasmic reticulum (ER) stress, which were detected by mitochondria and associated markers, by increasing the intracellular free Ca2+ level through the Piezo1 ion channel localized on the plasma membrane and ER membrane in NP cells. Besides, we proposed that intracellular free Ca2+ level elevation and the activation of ER stress are positive feedback processes that promote each other, consistent with the results that the level of ER stress in coccygeal discs of aged Piezo1-CKO mice were significantly lower than that of aged WT mice. Then, we confirmed that selenium supplementation decreased intracellular free Ca2+ level by mitigating ER stress through upregulating Selenoprotein K (SelK) expression. Besides, ferroptosis caused by the impaired production and function of Glutathione peroxidase 4 (GPX4) due to mechanical overloading-induced calcium overload could be improved by selenium supplementation through Se-GPX4 axis and Se-SelK axis in vivo and in vitro, eventually presenting the stabilization of the extracellular matrix (ECM). Our findings reveal the important role of ferroptosis in mechanical overloading-induced IVDD, and selenium supplementation promotes significance to attenuate ferroptosis and thus alleviates IVDD, which might provide insights into potential therapeutic interventions for IVDD.

The spatial arrangement of cells in a 3D-printed biomimetic spinal cord promotes directional differentiation and repairs the motor function after spinal cord injury.

Spinal cord injury is a permanent destructive disease that causes devastating neurologic deficits and disability. Long-term complications are associated with low prognosis, mortality, and decreased quality of life. The functional recovery depends on the regeneration of neurons and the growth of medullated axons. Single treatment strategies, including cell transplantation, cannot adapt to a changeable microenvironment. Patients with spinal cord injuries need more effective, long-term, and stable treatment options. Therefore, we investigated the benefit of a combined-tissue engineering strategy by loading homologous bone mesenchymal stem cells (BMSCs) and Schwann cells in three-dimensional (3D) scaffolds. We placed BMSCs and Rat Schwann cells (RSCs) in specific spatial arrangements using cell gravity and the diffusion effect to promote the formation of intercellular connections and cell-directed differentiation. This novel bioengineering system allowed us to control multiple factors, including cell types, cell relative position, and axon growth direction in the scaffold. Our system facilitated motor function recovery by enhancing tissue mimicry and allowing the reconstruction of medullated axons. This new 3D-integrated printing platform is multi-function and can simulate biomimetic tissue using different types of materials and multi-cells scaffolds. We believe that this study can help promote the clinical development and application of 3D printing in the field of regenerative medicine.

Dynamic Needle Tip Positioning versus Palpation and Ultrasound for Arteriovenous Puncture: A Meta-analysis.

At present, dynamic needle-tip positioning (DNTP) technology is applied in arteriovenous puncture, challenging the use of ultrasound technology alone and palpation. Our goals were to extract data from experimental DNTP, ultrasound and palpation studies, using Review Manager, Version 5.3, for data analysis, and to evaluate whether DNTP has certain advantages in puncture. PubMed, EMBASE, the Cochrane Library, CNKI and WanFang Data Knowledge Service Platform were searched for randomized and non-randomized studies that compared DNTP with conventional ultrasound-guided techniques, no DNTP or palpation. The risk ratio with 95% confidence interval was calculated using the model corresponding to the I² value. Studies were identified to compare clinical indexes. With respect to clinical indexes, DNTP is better in terms of first-attempt success, overall success and complications. However, in infants, first-attempt success, overall success and number of additional punctures did not indicate good efficacy for DNTP compared with palpation. Artery puncture was also not performed well under ultrasound. On the basis of the current evidence, the advantages of DNTP over palpation and ultrasound are reflected in the successful first attempt rate of all groups and in all subgroups except infants. Therefore, for emergencies in elderly patients, DNTP can be used as a general method. Given that some of the studies were of low quality, more trials of high quality should be conducted to further verify the findings.

Bioinformatic Analysis of Neuroimmune Mechanism of Neuropathic Pain.

BACKGROUND: Neuropathic pain (NP) is a devastating complication following nerve injury, and it can be alleviated by regulating neuroimmune direction. We aimed to explore the neuroimmune mechanism and identify some new diagnostic or therapeutic targets for NP treatment via bioinformatic analysis. METHODS: The microarray GSE18803 was downloaded and analyzed using R. The Venn diagram was drawn to find neuroimmune-related differentially expressed genes (DEGs) in neuropathic pain. Gene Ontology (GO), pathway enrichment, and protein-protein interaction (PPI) network were used to analyze DEGs, respectively. Besides, the identified hub genes were submitted to the DGIdb database to find relevant therapeutic drugs. RESULTS: A total of 91 neuroimmune-related DEGs were identified. The results of GO and pathway enrichment analyses were closely related to immune and inflammatory responses. PPI analysis showed two important modules and 8 hub genes: PTPRC, CD68, CTSS, RAC2, LAPTM5, FCGR3A, CD53, and HCK. The drug-hub gene interaction network was constructed by Cytoscape, and it included 24 candidate drugs and 3 hub genes. CONCLUSION: The present study helps us better understand the neuroimmune mechanism of neuropathic pain and provides some novel insights on NP treatment, such as modulation of microglia polarization and targeting bone resorption. Besides, CD68, CTSS, LAPTM5, FCGR3A, and CD53 may be used as early diagnostic biomarkers and the gene HCK can be a therapeutic target.