A novel strategy for spinal cord reconstruction via vascularized allogeneic spinal cord transplantation combine spinal cord fusion.

AIMS: Spinal cord injuries (SCI) pose persistent challenges in clinical practice due to the secondary injury. Drawing from our experience in spinal cord fusion (SCF), we propose vascularized allogeneic spinal cord transplantation (vASCT) as a novel approach for SCI, much like organ transplantation has revolutionized organ failure treatment and vascularized composite-tissue allotransplantation has addressed limb defects. MATERIALS AND METHODS: In this study, 24 dogs were paired and underwent vASCT, with donor spinal cord grafts and polyethylene glycol (PEG) application for SCF. The experimental group (n = 8) received tacrolimus and methylprednisolone, while the control group (n = 4) received only methylprednisolone. Safety and efficacy of vASCT were evaluated through electrophysiology, imaging, and 6-month follow-up. RESULTS: The experimental group showed substantial recovery in hind limb motor function. Imaging revealed robust survival of spinal cord grafts and restoration of spinal cord continuity. In contrast, the control group maintained hind limb paralysis, with imaging confirming spinal cord graft necrosis and extensive defects. Electrophysiologically, the experimental group exhibited restored motor evoked potential signal conduction postoperatively, unlike the control group. Notably, PEG application during vASCT led to signal conduction recovery in intraoperative spinal cord evoked potential examinations for all dogs. CONCLUSION: In the vASCT surgical model, the combination of PEG with tacrolimus has demonstrated the ability to reconstruct spinal cord continuity and restore hind limb motor function in beagles. Notably, a low dose of tacrolimus has also exhibited an excellent anti-immune rejection effect. These findings highlight vASCT's potential promise as a therapeutic strategy for addressing irreversible SCI.

Developing preclinical dog models for reconstructive severed spinal cord continuity via spinal cord fusion technique.

Background: Spinal cord injury (SCI) is a severe impairment of the central nervous system, leading to motor, sensory, and autonomic dysfunction. The present study investigates the efficacy of the polyethylene glycol (PEG)-mediated spinal cord fusion (SCF) techniques, demonstrating efficacious in various animal models with complete spinal cord transection at the T10 level. This research focuses on a comparative analysis of three SCF treatment models in beagles: spinal cord transection (SCT), vascular pedicle hemisected spinal cord transplantation (vSCT), and vascularized allograft spinal cord transplantation (vASCT) surgical model. Methods: Seven female beagles were included in the SCT surgical model, while four female dogs were enrolled in the vSCT surgical model. Additionally, twelve female dogs underwent vASCT in a paired donor-recipient setup. Three surgical model were evaluated and compared through electrophysiology, imaging and behavioral recovery. Results: The results showed a progressive recovery in the SCT, vSCT and vASCT surgical models, with no statistically significant differences observed in cBBB scores at both 2-month and 6-month post-operation (both P>0.05). Neuroimaging analysis across the SCT, vSCT and vASCT surgical models revealed spinal cord graft survival and fiber regrowth across transection sites at 6 months postoperatively. Also, positive MEP waveforms were recorded in all three surgical models at 6-month post-surgery. Conclusion: The study underscores the clinical relevance of PEG-mediated SCF techniques in promoting nerve fusion, repair, and motor functional recovery in SCI. SCT, vSCT, and vASCT, tailored to specific clinical characteristics, demonstrated similar effective therapeutic outcomes.

Partial Restoration of Spinal Cord Neural Continuity via Sural Nerve Transplantation Using a Technique of Spinal Cord Fusion.

BACKGROUND: Spinal cord injury (SCI) can cause paralysis and serious chronic morbidity, and there is no effective treatment. Based on our previous experimental results of spinal cord fusion (SCF) in mice, rats, beagles, and monkeys, we developed a surgical protocol of SCF for paraplegic human patients. We designed a novel surgical procedure of SCF, called sural nerve transplantation (SNT), for human patients with lower thoracic SCI and distal cord dysfunction. METHODS: We conducted a clinical trial (ChiCTR2000030788) and performed SNT in 12 fully paraplegic patients due to SCI between T1 and T12. We assessed pre- and postoperative central nerve pain, motor function, sensory function, and autonomic nerve function. Conduction of action potentials across the sural nerve transplant was evaluated. Neural continuity was also examined by diffusion tensor imaging (DTI). RESULTS: Among the 12 paraplegic patients enrolled in this clinical trial, seven patients demonstrated improved autonomic nerve functions. Seven patients had clinically significant relief of their symptoms of cord central pain. One patient, however, developed postoperative cord central pain (VAS: 4). Five patients had varying degrees of recovered sensory and/or motor functions below the single neurologic level 1 month after surgery. One patient showed recovery of electrophysiologic, motor-evoked potentials 6 months after the operation. At 6 months after surgery, DTI indicated fusion and nerve connections of white cord and sural nerves in seven patients. CONCLUSION: SNT was able to fuse the axonal stumps of white cord and sural nerve and at least partially improve the cord central pain in most patients. Although SNT did not restore the spinal cord continuity in white matter in some patients, SNT could restore spinal cord continuity in the cortico-trunco-reticulo-propriospinal pathway, thereby restoring in part some motor and sensory functions. SNT may therefore be a safe, feasible, and effective method to treat paraplegic patients with SCI. Future clinical trials should be performed to optimize the type/technique of nerve transplantation, reduce surgical damage, and minimize postoperative scar formation and adhesion, to avoid postoperative cord central pain. CLINICAL TRIAL REGISTRATION: [http://www.chictr.org.cn/showproj.aspx?proj=50526], identifier [ChiCTR2000030788].

TGFß1 is essential for MSCs-CAFs differentiation and promotes HCT116 cells migration and invasion via JAK/STAT3 signaling.

BACKGROUND AND PURPOSE: Colorectal cancer (CRC) frequently metastasizes to the liver, which involves the participation of multiple cytokines. Tumor microenvironment (TME) composed of cancer-associated fibroblasts (CAFs) and tumor cells acts as an essential factor in cancer metastasis. Transforming growth factor ß1 (TGFß1) is a vital cytokine involved in migration and invasion of cancer cells. However, the underlying mechanisms remain unclear. In the present study, we aimed to investigate the role and molecular mechanisms of TGFß1 in TME. METHODS: The conditioned medium prepared from colorectal cancer HCT116 and HT29 cells was used to culture mesenchymal stem cells (MSCs). The differentiation of MSCs to CAFs was detected by flow cytometry. The role of TGFß1 in colorectal cancer cells metastasis was examined by wound-healing assay and transwell assay. And the activation of the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling pathway was measured by Western blot assay. RESULTS: TGFß1 induced the differentiation of MSCs to CAFs and improved HCT116 and HT29 cells migration and invasion. Meanwhile, TGFß1 also upregulated the phosphorylation of STAT3 and enhanced the nuclear localization of p-STAT3, which activated JAK/STAT3 signaling pathway. CONCLUSION: TGFß1 induced the differentiation of MSCs into CAFs and promoted the migration and invasion of HCT116 and HT29 cells, which depended on the activation of JAK/STAT3 signaling pathway.

Correlations of MRI manifestations with survivin gene expression in primary hepatic carcinoma.

OBJECTIVE: To investigate the correlations of magnetic resonance imaging (MRI) manifestations with survivin gene expression in primary hepatocellular carcinoma (HCC). METHODS: A total of 84 HCC patients receiving partial hepatectomy in the Surgery Department and Oncology Department in our hospital from April 2011 to May 2014 were recruited. At 1 week before operation, MRI was used to examine the imaging features of liver, a certain size of area was defined and the signal value of each sequence was recorded. HCC and para-carcinoma tissues were collected after operation, and the expression levels of survivin were detected via immunohistochemistry (IHC). All patients were followed up for 30 months after operation, and the Kaplan-Meier survival curve was drawn. The correlations of survivin expression with MRI features and signal parameters of each sequence were analyzed. RESULTS: There was no expression of survivin in normal liver tissues. In HCC and para-carcinoma tissues, the nuclei of positive cells showed brown yellow. The positive expression rate of survivin in HCC tissues was 76.19% (64/84), which was significantly higher than that in para-carcinoma tissues (20.81%, 20/84) (p< 0.05). The overall survival (OS) of patients with high expression of survivin was 12.5 months, which was significantly shorter than that of patients with low expression of survivin (17.6 months) (p< 0.05). Results of chi-square test showed that the survivin level had no correlations with the MRI scan shape and edge in the tumor area (p> 0.05), but it was significantly correlated with tumor diameter, MRI enhancement features and lymphatic metastasis (p< 0.05). Pearson correlation analyses revealed that the survivin IHC score was not correlated with in-phase T1-weighted gradient-recalled echo (GRE), hepatic arterial-phase T1-weighted GRE, portal venous-phase T1-weighted GRE and equilibrium-phase T1-weighted GRE signals (p> 0.05). Besides, the survivin IHC score was negatively correlated with opposed-phase T1-weighted GRE (r=-0.46, p= 0.038), but positively correlated with T2-weighted fast spin echo signal (r=-0.49, p= 0.025). CONCLUSION: Survivin is significantly up-regulated in HCC tissues and associated with tumor growth and lymph node metastasis. Clinical detection of survivin level combined with MRI examination might be beneficial for clinical diagnosis and treatment of HCC.

[Clinical application and value of 3 Tesla contrast enhanced whole-heart coronary magnetic resonance angiography].

OBJECTIVE: To investigate the clinical application, feasibility and value of 3 T whole-heart contrast enhanced free-breathing navigator-gated three-dimensional coronary magnetic resonance angiography (CE-CMRA). METHODS: 3 T CE-CMRA was used to examine patients with suspected coronary heart disease (CAD). Gd-BOPTA (0.2 mmol/kg) was injected intravenously with slow infusion rate (0.3 ml/s) to perform enhancement. Data were post-processed to obtain principal branches of coronary artery and picture quality was evaluated. According to results of selective coronary arteriography (SCAG), the diagnostic accuracy of CE-CMRA for diagnosing CAD was judged by means of detecting significant stenosis (> 50%) of the principal branches based on the 9 segments of coronary artery. RESULTS: Twenty-three out of 26 patients successfully completed the examination. The mean scanning time was (10.4 ± 2.1) minutes, 178 out of 202 (88.1%) SCAG demonstrated segments could be evaluated by CE-CMRA. The imaging quality was superior in proximal and middle segments of coronary artery principal branches than in distal segments. Based on patient-level, there were 9 positive cases and 14 negative cases examined by CE-CMRA compared with 11 positive cases and 12 negative cases examined by SCAG, respectively. The whole diagnose accordance rate of CE-CMRA was 91.3% (21/23) compared with SCAG. The sensitivity, specificity and negative predictive values were 81.8% (9/11), 88.5% (169/191) and 98.8% (9/31) respectively. CONCLUSIONS: 3 T CE-CMRA is a feasible non-invasive imaging modality for diagnosing CAD, especially to detect significant stenosis in proximal and middle segments of coronary artery principal branches. However, the detecting efficacy is limited in assessing stenosis of distal segment and small branches of coronary artery.