Neural Regeneration Research ›› 2025, Vol. 20 ›› Issue (5): 1467-1482.doi: 10.4103/NRR.NRR-D-23-01338

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Chondroitinase ABC combined with Schwann cell transplantation enhances restoration of neural connection and functional recovery following acute and chronic spinal cord injury

Wenrui Qu1, 2 , Xiangbing Wu1 , Wei Wu1 , Ying Wang1 , Yan Sun1 , Lingxiao Deng1 , Melissa Walker 1 , Chen Chen1 , Heqiao Dai 1 , Qi Han1 , Ying Ding1 , Yongzhi Xia1 , George Smith3 , Rui Li 2 , Nai-Kui Liu1, * , Xiao-Ming Xu1, 4, *, †   

  1. 1 Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Instttute, Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN, USA;  2 Department of Hand Surgery, the Second Hospital of Jilin University, Changchun, Jilin Province, China;  3 Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA, USA;  4 Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA
  • Online:2025-05-15 Published:2024-10-31
  • Contact: Nai-Kui Liu, MD, PhD, nailiu@iupui.edu; Xiao-Ming Xu, MD, PhD, xu26@iupui.edu.
  • Supported by:
    This work was supported in part by NIH R01 NS100531, R01 NS103481, Merit Review Award I01 BX002356, I01 BX003705 from the U.S. Department of Veterans Affairs, Indiana Spinal Cord and Brain Injury Research Foundatton (No. 19919), Mari Hulman George Endowment Funds (to XMX), Indiana Spinal Cord & Brain Injury Research Fund from ISDH (to NKL and LD) and NIH R21NS130241 (to LD).

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Abstract:

Schwann cell transplantation is considered one of the most promising cell-based therapy to repair injured spinal cord due to its unique growth-promoting and myelin-forming properties. A the Food and Drug Administration-approved Phase I clinical trial has been conducted to evaluate the safety of transplanted human autologous Schwann cells to treat patients with spinal cord injury. A major challenge for Schwann cell transplantation is that grafted Schwann cells are confined within the lesion cavity, and they do not migrate into the host environment due to the inhibitory barrier formed by injury-induced glial scar, thus limiting axonal reentry into the host spinal cord. Here we introduce a combinatorial strategy by suppressing the inhibitory extracellular environment with injection of lentivirus-mediated transfection of chondroitinase ABC gene at the rostral and caudal borders of the lesion site and simultaneously leveraging the repair capacity of transplanted Schwann cells in adult rats following a mid-thoracic contusive spinal cord injury. We report that when the glial scar was degraded by chondroitinase ABC at the rostral and caudal lesion borders, Schwann cells migrated for considerable distances in both rostral and caudal directions. Such Schwann cell migration led to enhanced axonal regrowth, including the serotonergic and dopaminergic axons originating from supraspinal regions, and promoted recovery of locomotor and urinary bladder functions. Importantly, the Schwann cell survival and axonal regrowth persisted up to 6 months after the injury, even when treatment was delayed for 3 months to mimic chronic spinal cord injury. These findings collectively show promising evidence for a combinatorial strategy with chondroitinase ABC and Schwann cells in promoting remodeling and recovery of function following spinal cord injury. 

Key words:

axonal regrowth, bladder function, chondroitinase ABC, functional recovery, glial scar, lentivirus, migration, Schwann cell, spinal cord injury, transplantation