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

Abstract

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.

Cell therapy for spinal cord injury by using human iPSC-derived region-specific neural progenitor cells

“…This is also consistent with a previous report in which SC-type fetal NPC engraftment was shown to improve the motor function of SCI mice with mild lesions but not severe lesions [ 14 ]. The importance of lesion severity is also highlighted by the recent finding that treatment with anti-HMGB1 antibody reduced the lesion size of the injured spinal cord and improved motor function recovery synergistically with NPC transplantation [ 34 ]. To exploit the full potential of NPCs for SCI treatment, the use of such an additional approach to minimize the lesion size will be important.…”

HMGB1 Translocation in Neurons after Ischemic Insult: Subcellular Localization in Mitochondria and Peroxisomes

“…High mobility group box-1 (HMGB1) is released from neurons during ischemic injury, traumatic injury, intracerebral hemorrhage, and spinal cord injury [1][2][3][4][5][6]. The translocation of HMGB1 in neurons and their subsequent release were demonstrated in primary culture after the insult of glucose deprivation and glutamate treatment [7,8].…”

Polycaprolactone electrospun fiber scaffold loaded with iPSCs-NSCs and ASCs as a novel tissue engineering scaffold for the treatment of spinal cord injury

“…Based on the different treatments, 60 Wistar rats were divided into four experimental groups, in order to minimize the sacrifice and suffering of animals, we refer to previous experiments and cancel the sham operation group. 28 The control group is Group Adult female Wistar rats (230-250 g) were used for spinal cord transection. Animals were acclimatized for at least one weeks before surgery.…”

“…25 While several studies have shown that single SC repair of SCI is still limited, researchers try to transplant it with other stem cells in order to achieve better effects. [26][27][28] Coculture of SCs with neural stem cells (NSCs) can remarkably increase the proportion of neuron differentiation and effectively improve the recovery of nerve endings. 29 Polycaprolactone (PCL) is an aliphatic, biodegradable, nontoxic polyester with good mechanical properties.…”