中国神经再生研究(英文版) ›› 2025, Vol. 20 ›› Issue (5): 1467-1482.doi: 10.4103/NRR.NRR-D-23-01338

• 原著:脊髓损伤修复保护与再生 • 上一篇    下一篇

许旺细胞和硫酸软骨素酶ABC联合移植促进急慢性脊髓损伤后神经连接恢复和功能恢复

  

  • 出版日期:2025-05-15 发布日期:2024-10-31
  • 基金资助:
    美国国立卫生研究院 R01 NS100531,R01 NS103481; 美国退伍军人事务部 I01 BX002356,I01 BX003705;印第安纳州脊髓和脑损伤研究基金会(第 19919 号); Mari Hulman George 捐赠基金; ISDH 的印第安纳州脊髓和脑损伤研究基金以及美国国立卫生研究院 R21NS130241资助

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).

摘要:

许旺细胞移植因其独特的促进生长和形成髓鞘的特性,被认为是修复损伤脊髓的最有前途的细胞疗法之一。但由于损伤引起的胶质瘢痕形成的抑制屏障,移植的许旺细胞不会迁移到宿主环境中,从而限制了轴突重新长入宿主脊髓。实验引入了一种组合策略,即将许旺细胞移植到脊髓损伤部位并同时在病变部位的喙侧和尾侧注射慢病毒软骨素酶ABC。结果显示,当软骨素酶ABC在病变喙侧和尾侧边界降解神经胶质瘢痕时,许旺细胞向喙侧和尾侧方向迁移了相当长的距离。这种许旺细胞迁移增强了轴突再生,包括源自脊髓上区的5-羟色胺能和多巴胺能轴突,并促进了运动和膀胱功能的恢复。重要的是,即使治疗延迟3个月以模拟慢性脊髓损伤,许旺细胞的存活和轴突生长在损伤后6个月仍能持续。以上结果表明,在促进脊髓损伤后的神经修复和功能恢复方面,许旺细胞和硫酸软骨素酶ABC联合移植策略大有可为。

https://orcid.org/0000-0003-3195-6489 (Nai-Kui Liu); https://orcid.org/0000-0002-7229-0081 (Xiao-Ming Xu)

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