Prior Treatment with Anti-High Mobility Group Box-1 Antibody Boosts Human Neural Stem Cell Transplantation-Mediated Functional Recovery After Spinal Cord Injury.

Together with residual host neurons, transplanted neural stem cell (NSC)-derived neurons play a critical role in reconstructing disrupted neural circuits after spinal cord injury (SCI). Since a large number of tracts are disrupted and the majority of host neurons die around the lesion site as the damage spreads, minimizing this spreading and preserving the lesion site are important for attaining further improvements in reconstruction. High mobility group box-1 (HMGB1) is a damage-associated molecular pattern protein that triggers sterile inflammation after tissue injury. In the ischemic and injured brain, neutralization of HMGB1 with a specific antibody reportedly stabilizes the blood-brain barrier, suppresses inflammatory cytokine expression, and improves functional recovery. Using a SCI model mouse, we here developed a combinatorial treatment for SCI: administering anti-HMGB1 antibody prior to transplantation of NSCs derived from human induced pluripotent stem cells (hiPSC-NSCs) yielded a dramatic improvement in locomotion recovery after SCI. Even anti-HMGB1 antibody treatment alone alleviated blood-spinal cord barrier disruption and edema formation, and increased the number of neurites from spared axons and the survival of host neurons, resulting in functional recovery. However, this recovery was greatly enhanced by the subsequent hiPSC-NSC transplantation, reaching an extent that has never before been reported. We also found that this improved recovery was directly associated with connections established between surviving host neurons and transplant-derived neurons. Taken together, our results highlight combinatorial treatment with anti-HMGB1 antibody and hiPSC-NSC transplantation as a promising novel therapy for SCI. Stem Cells 2018;36:737-750.

Revision total hip arthroplasty using a Kerboull-type acetabular reinforcement device and allogeneic structural bone graft.

PURPOSE: One of the major problems in revision total hip arthroplasty (THA) is severe acetabular bone loss. The aim of our study was to evaluate the clinical outcomes of revision THA using a Kerboull-type reinforcement device (KT plate) and allogeneic structural bone graft. METHODS: This retrospective study evaluated 48 hips that underwent revision THA using a KT plate and allogeneic structural bone graft between 2008 and 2016, with a median follow-up of 6.2 years (range 3-12.6 years). Functional outcome was assessed using the Japanese Orthopaedic Association (JOA) hip score. Postoperative and follow-up radiographs were compared to assess migration and breakage of the implant. RESULTS: The mean JOA hip score improved from 45.6 (±16.3) points before surgery to 72.1 (±11.9) points at the most recent follow-up examination (p < 0.001). Two hips (4.2%) underwent re-revision THA because of cup loosening due to breakage of the KT plate. A total of 13 hips (27.1%) were classified as radiological failures. Binomial logistic regression analysis showed that a Kawanabe classification of stage 4, which indicates massive bone defects in the weight-bearing area, was a risk factor for radiological failure (odds ratio: 4.57; 95% confidence interval: 1.01-26.35). CONCLUSIONS: A KT plate with an allogeneic structural bone graft is a useful method of acetabular reconstruction in revision THA that restores bone stock and improves hip function. Our findings indicated that a Kawanabe classification of stage 4 was a risk factor for radiological failure of the implant.

Combinatrial treatment of anti-High Mobility Group Box-1 monoclonal antibody and epothilone B improves functional recovery after spinal cord contusion injury.

Spinal cord injury (SCI) causes motor and sensory deficits and is currently considered an incurable disease. We have previously reported that administration of anti-High Mobility Group Box-1 monoclonal antibody (anti-HMGB1 mAb) preserved lesion area and improved locomotion recovery in mouse model of SCI. In order to further enhance the recovery, we here examined combinatorial treatment of anti-HMGB1 mAb and epothilone B (Epo B), which has been reported to promote axon regeneration. This combinatorial treatment significantly increased hindlimb movement compared with anti-HMGB1 mAb alone, although Epo B alone failed to increase functional recovery. These results are in agreement with that anti-HMGB1 mAb alone was able to decrease the lesion area spreading and increase the surviving neuron numbers around the lesion, whereas Epo B facilitated axon outgrowth only in combination with anti-HMGB1 mAb, suggesting that anti-HMGB1 mAb-dependent tissue preservation is necessary for Epo B to exhibit its therapeutic effect. Taken together, the combinatorial treatment can be considered as a novel and clinically applicable strategy for SCI.

Therapeutic time window of anti-high mobility group box-1 antibody administration in mouse model of spinal cord injury.

Spinal cord injury (SCI) is a devastating neurologic disorder that often leads to permanent disability, and there is no effective treatment for it. High mobility group box-1 (HMGB1) is a damage-associated molecular protein that triggers sterile inflammation upon injuries. We have previously shown that two administrations of neutralizing monoclonal antibody (mAb) against HMGB1 (immediately after (0 h) and 6 h after) SCI dramatically improves functional recovery after SCI in mice. However, when considering clinical application, 0 h after SCI is not practical. Therefore, in this study, we examined the therapeutic time window of the mAb administration. Injection at 3 h after SCI significantly improved the functional recovery comparably to injection immediately after SCI, while injection at 6 h was less effective, and injection at 9 or 12 h had no therapeutic effect. We also found beneficial effects of injection at 3 h after injury on blood-spinal cord barrier maintenance, inflammatory-related gene expression and preservation of the damaged spinal cord tissue. Taken together, our results suggest that a single administration of anti-HMGB1 mAb within a proper time window could be a novel and potential therapeutic strategy for SCI.