Background After wide range of traumatic damage to the spinal cord, reactive astrocytes migrate toward the lesion but stop at the edge of the fibrotic extracellular matrix (ECM) core. There, the reactive astrocytes accumulate and form the glial scar border that prevents the regenerating axons from passing through. Why these astrocytes stop at this border rather than entering the ECM remains unknown. We reasoned that this stop signal comes from the fibrotic ECM. Among its components, we focused on type III collagen, which is abundant in the core but whose role in scar formation is unknown. Methods We analyzed single-nucleus RNA-sequencing and spatial transcriptomic datasets of mouse spinal cords. Using cell-cell interaction analysis, we searched for the astrocyte receptor that binds type III collagen. We then tested the candidate pathway in primary astrocytes in vitro , in vivo using pharmacological and genetic inhibition, and in human induced pluripotent stem cell (hiPSC)-derived astrocytes. Results We found six astrocyte subclusters that changed over time. Among them, reactive astrocytes showed a strong interaction between type III collagen, encoded by Col3a1 , and adhesion G protein-coupled receptor G1 (ADGRG1). Col3a1 -expressing vascular leptomeningeal cells (VLMCs) and arachnoid barrier cells (ABCs) sat next to ADGRG1-expressing astrocytes at the fibrotic border. In vitro , type III collagen activated RhoA-GTP loading through ADGRG1 and suppressed astrocyte migration. This effect was specific to type III collagen and was reversed by the ADGRG1 antagonist Dihydromunduletone (DHM). In vivo , both pharmacological inhibition of ADGRG1 and astrocyte-specific Adgrg1 knockdown let astrocytes enter the type III collagen-rich matrix. This produced smaller glial scars, enhanced corticospinal tract (CST) regeneration, and improved motor recovery. The same response occurred in hiPSC-derived astrocytes. Conclusions Type III collagen keeps astrocytes at the edge of the fibrotic ECM and stops them from entering it, acting through ADGRG1–RhoA signaling. This sets the position of the glial scar border. The type III collagen–ADGRG1 axis may be a new therapeutic target for controlling maladaptive scarring after CNS injury.
BACKGROUND:The survivors from crush syndrome are often disabled due to the affected limbs, with excessive fibrosis changes at damaged muscle tissue. We previously reported that a zinc chelator (N,N,N',N'-tetrakis-(2-pyridylmethyl)-ethylenediamine: TPEN) administration to the crush syndrome mice model inhibited neutrophil activation induced by ischemia-reperfusion, alleviating the inflammatory response. In the present study, we investigated the effects of TPEN administration on fibrosis in affected limb muscles. METHODS:Eight-week-old C57BL/6J mice were subjected to bilateral hindlimb compression using a rubber tourniquet for 2 h to create a crush syndrome model. Compression was then released to allow reperfusion. Gait evaluations and muscle tissue analyses were performed up to 4 weeks post-reperfusion. We investigated the effects of TPEN administration on functional recovery and histopathology of the affected muscles. RESULTS:In the chronic phase of the crush syndrome model, the gait function was impaired owing to muscle tissue fibrosis. The affected muscle tissue sustained sarcolemma hyperpermeability caused by basement membrane disruption and mitochondrial fission, resulting from elevated neutrophil elastase expression. In muscle tissue, PECAM-1-positive vascular endothelial cells co-expressed Notch1 and αSMA, indicating induction of endothelial-to-mesenchymal transition (EndMT) was occurring following persistent mitochondrial fission. TPEN administration reduced neutrophil elastase expression, improving the sarcolemma integrity due to the reduced infiltration of neutrophils. This led to the inhibition of EndMT, which minimized fibrosis and accelerated muscle regeneration, allowing for better functional recovery. CONCLUSIONS:This study demonstrates that zinc chelator administration not only alleviates fibrosis in muscle tissues damaged by crush syndrome but also stimulates tissue regeneration in the chronic phase. Our findings provide insight into the mechanism of muscle fibrosis and may represent a breakthrough in the treatment of crush syndrome, potentially minimizing long-term disability in the affected limbs.
OBJECTIVE:To quantify changes in the EuroQol 5-Dimension (EQ-5D) index value associated with clinically important functional improvement in patients with traumatic spinal cord injury (SCI). DESIGN:Secondary longitudinal analysis. SETTING:SCI center in Japan using data from the Japan Single-Center Study for Spinal Cord Injury Database. PARTICIPANTS:Patients with traumatic SCI (N=163) registered in the Japan Single-Center Study for Spinal Cord Injury Database between 2015 and 2024. INTERVENTIONS:Not applicable. MAIN OUTCOME MEASURES:The primary patient-reported outcome was the EQ-5D index value from the EuroQol 5-Dimension 5-Level questionnaire at 2 weeks and 3 months after injury. As reference measures, we used previously reported minimal important change thresholds for the Spinal Cord Independence Measure version III (SCIM-III) subscale scores to compare EQ-5D index value changes between improvement and nonimprovement groups. Patients were classified into improvement and nonimprovement groups for the Walking Index for SCI version II and for upper and lower extremity motor scores derived from the International Standards for Neurological Classification of SCI motor score, based on established smallest real difference values; these were evaluated as supportive indices. Using these classifications, receiver operating characteristic analyses identified EQ-5D index value change thresholds. RESULTS:In patients with cervical SCI (American Spinal Injury Association Impairment Scale C/D), analyses using previously reported Spinal Cord Independence Measure version III subscale minimal important change thresholds yielded EQ-5D index value change thresholds of 0.182 (95% confidence interval, 0.112-0.253) for "self-care" and 0.173 (95% confidence interval, 0.107-0.284) for "respiration and sphincter management." Other functional measures did not meet criteria for anchor validity and were not used to identify EQ-5D thresholds. CONCLUSIONS:In patients with cervical SCI with incomplete motor paralysis, this study quantitatively demonstrated the extent to which functional recovery is reflected in changes in EQ-5D index values. The findings provide reference thresholds to support clinical interpretation of EQ-5D index changes in the SCI field.
OBJECTIVES:To investigate the prognostic value of the Zone of Partial Preservation (ZPP) within 72 h after cervical spinal cord injury (CSCI) with the American Spinal Injury Association Impairment Scale (AIS) A, and to examine the utility of combining magnetic resonance imaging (MRI) findings with ZPP assessment. STUDY DESIGN:A retrospective case series. SETTING:Our institute. PARTICIPANTS/METHODS:The study participants were seventy patients with an initial diagnosis of complete CSCI within 72 h after injury. The impact of sensory or motor ZPP lengths on the rates of conversion to AIS B/C/D and sensory and motor score recovery at three months after injury was investigated. MRI-based sensory/motor ZPP length was defined as the number of segments between the sensory/motor ZPP and the presumptive primary injured segment of the spinal cord inferred from MRI, and its relevance was also investigated. RESULTS:A total of 9 improved to AIS B, 6 to C, and 1 to D. Sensory ZPP length ≥ 12, and MRI-based sensory ZPP length ≥ 10 were predictive of conversion to AIS C/D with an odds ratio of 18.5 (95% CI, 2.2-154.0, p < 0.05). Significantly greater motor score gain was demonstrated in individuals with longer lengths of MRI-based sensory ZPP (p < 0.05). CONCLUSION:Long sensory ZPP length within 72 h after injury could be a prognostic factor of conversion to AIS C/D and motor score gain in individuals with sensorimotor complete CSCI. ZPPs could be more useful for predicting recovery potential when combined with MRI findings.
Aims The aim of this study was to compare neurological outcomes achieved by two systems of spinal cord injury care: that which was developed by the National Spinal Injuries Centre, Stoke Mandeville Hospital, UK (predominantly conservative, 10% to 15% treated with surgical stabilization, most with gradual mobilization) and that which is practised by USA centres contributing data to the Spinal Cord Injury Model Systems (SCIMS) database (predominantly surgical, often > 80% undergoing surgical stabilization, most with rapid mobilization). Methods Neurological outcomes from 608 patients treated at Stoke Mandeville between 1951 and 1968, and 300 patients treated using the Stoke Mandeville system at Colmar-Mulhouse and Basel (France and Switzerland) between 1968 and 1978, were compared with 804 patients admitted to SCIMS rehabilitation centres between 2011 and 2018. The stratified Mann-Whitney U test was used for overall neurological outcomes; subgroups were tested for differences in proportions. Results Both Stoke Mandeville system centres achieved significantly better Frankel grade neurological outcomes compared with SCIMS centres (Stoke Mandeville, p < 0.001; Colmar-Mulhouse and Basel, p < 0.001). Had the 804 patients treated at SCIMS centres in the USA achieved the outcomes which were achieved using the Stoke Mandeville system, between 71 and 87 fewer might have deteriorated neurologically, between 195 and 330 more patients might have walked again, and between 129 and 264 more patients might have been completely cured, with no sensory or motor loss and no sphincter disturbance. Conclusion The Stoke Mandeville system of spinal cord injury care should not have been rejected without clinical trials. Cite this article: Bone Joint J 2026;108-B(3):425–430.
